WO2008089258A2 - Drug eluting medical device using polymeric therapeutics - Google Patents

Drug eluting medical device using polymeric therapeutics Download PDF

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Publication number
WO2008089258A2
WO2008089258A2 PCT/US2008/051196 US2008051196W WO2008089258A2 WO 2008089258 A2 WO2008089258 A2 WO 2008089258A2 US 2008051196 W US2008051196 W US 2008051196W WO 2008089258 A2 WO2008089258 A2 WO 2008089258A2
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composition
polymer
pharmaceutically active
chemical moiety
active agent
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PCT/US2008/051196
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French (fr)
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WO2008089258A3 (en
Inventor
Shrirang Ranade
Mark Steckel
Rachit Ohri
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Cappella, Inc.
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Publication of WO2008089258A2 publication Critical patent/WO2008089258A2/en
Publication of WO2008089258A3 publication Critical patent/WO2008089258A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6957—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a device or a kit, e.g. stents or microdevices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/593—Polyesters, e.g. PLGA or polylactide-co-glycolide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/605—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the macromolecule containing phosphorus in the main chain, e.g. poly-phosphazene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid

Definitions

  • the present invention relates to coatings for medical devices, such as implantable medical devices comprising biodegradable polymers that upon hydrolysis, form one or more pharmaceutically active agents.
  • Restenosis is a complex disease state that is being treated by drug eluting stents (DES).
  • DES drug eluting stents
  • commercially available DES comprise a coated stent where the coating includes a single drug eluted from a polymeric carrier.
  • One embodiment provides a composition comprising a biodegradable polymer, the biodegradable polymer being linked to a chemical moiety through a covalent bond, wherein, the chemical moiety forms a pharmaceutically active agent upon degradation of the covalent bond, and the composition is less soluble in an aqueous medium than the free form of the pharmaceutically active agent.
  • the polymer has a Tg greater than 37°C, e.g., greater than 40°C, greater than 50°C, or even greater than 60°C.
  • the covalent bond is hydrolytically degradable.
  • the composition is used for at least one coating for an implantable medical device, the at least one coating covering at least a portion of the device.
  • the biodegradable polymer comprises at least one monomeric unit selected from lactic acid, glycolic acid, caprolactone, lactide, glycolide, and thmethyl carbonate.
  • implantable medical device having at least one coating covering at least a portion of the device, the at least one coating including a compound comprising a biodegradable polymer linked to a chemical moiety through a covalent bond, wherein the chemical moiety forms a pharmaceutically active agent upon degradation of the covalent bond, and wherein the compound has a Tg greater than 37°C, e.g., greater than 40°C, greater than 50°C, or even greater than 60°C.
  • the chemical moiety is linked to the biodegradable polymer via a linking group.
  • the covalent bond is selected from anhydride and ester bonds.
  • the chemical moiety is linked to the biodegradable polymer as a pendant group of the polymer chain.
  • the chemical moiety is a portion of the polymer backbone.
  • the covalent bond is hydrolytically degradable.
  • the pharmaceutically active agent is selected from taxanes, limus derivatives, and non-steroidal anti-inflammatory agents.
  • the pharmaceutically active agent is selected from paclitaxel, sirolimus, everolimus, and biolimus.
  • the compound is less soluble than the free form of the pharmaceutically active agent.
  • the biodegradable polymer is present in an amount ranging from 40% to 95% by weight relative to the total weight of the composition.
  • the pharmaceutically active agent is present in a dose density ranging from 0.05 to 10 ⁇ g/mm 2 .
  • the number average molecular weight of the polymer is 20,000 Da or less, such as a number average molecular weight of 10,000 Da or less, or 5,000 Da or less. In one embodiment, the number average molecular weight of the polymer ranges from 5,000 daltons to 100,000 daltons. In another embodiment, the number average molecular weight of the polymer is 25,000 Da or less. In yet another embodiment, the number average molecular weight of the polymer ranges from 25,000 daltons to 100,000 daltons.
  • the at least one coating comprises at least two coatings to provide a multi-layered structure.
  • the at least one coating comprises at least three coatings.
  • each of the at least three coatings provides a different chemical moiety that forms a different pharmaceutically active agent.
  • the composition in one of the at least three coatings comprises a chemical moiety that forms an antiproliferative pharmaceutically active agent.
  • the composition in one of the at least three coatings comprises a chemical moiety that forms an anti-inflammatory agent.
  • the composition in one of the at least three coatings comprises a chemical moiety that forms a healing promoter.
  • the at least one coating directly contacts the device.
  • an inner coating free of a pharmaceutically active agent that directly contacts the device wherein the inner coating also directly contacts the at least one coating.
  • the device is implantable into a mammalian lumen.
  • the device is a stent.
  • the stent is either balloon expandable or self-expanding.
  • the composition is coated on the stent to form a conformal coating around all surfaces of the stent.
  • the composition is coated only on the abluminal surface of the stent. In one embodiment, the composition is coated only on the abluminal surface of the stent and the composition resides partially or completely within micro-reservoirs or pores in the stent surface.
  • the device is selected from pacemaker leads, valve replacement and repair devices, vena cava filters, and embolic coils and beads.
  • the device is an angioplasty balloon having coated thereon the coating comprising the composition, wherein the balloon is used to deliver the composition to an endoluminal surface.
  • the polymer has a Tg greater than 40°C. In one embodiment, the polymer has a Tg greater than 50°C, or greater than 60°C.
  • the biodegradable polymer is a blend comprising 15-85 weight percent PLGA relative to the total weight of the biodegradable polymer.
  • the blend further comprises D 1 L-PLA.
  • the polymer comprises D 1 L-PLA.
  • Another embodiment provides a polymer comprising the repeat unit:
  • L 1 , L 2 , and L 3 can be the same or different, and each are linking groups capable of covalently bonding to at least one of Di, D 2 , and BP,
  • Di is a chemical moiety that upon degradation of covalent bonds binding it to a linking group and BP, forms an antiproliferative pharmaceutically active agent
  • D 2 is a chemical moiety that upon degradation of covalent bonds binding it to linking group, forms an anti-inflammatory agent
  • D 3 is a chemical moiety that upon degradation of covalent bonds binding it to linking groups, forms a healing promoter
  • BP is a biodegradable polymer.
  • the polymer forms at least one coating covering at least a portion of an implantable medical device.
  • BP is chosen from PGLA and D 1 L-PLA.
  • Another embodiment provides a polymer comprising the repeat unit:
  • L 1 is a linking group capable of covalently bonding to at least one of D 1 and BP,
  • D 1 is a chemical moiety that upon degradation of the polymer, forms a pharmaceutically active agent
  • BP is a biodegradable polymer.
  • the polymer is less soluble in an aqueous medium than is the free form of the pharmaceutically active agent.
  • Another embodiment provides a polymer comprising the repeat unit:
  • L 1 and L 2 can be the same or different, and each are linking groups capable of covalently bonding to at least one of D 1 and BP, D 1 is a chemical moiety that upon degradation of the polymer, forms a pharmaceutically active agent, and
  • BP is a biodegradable polymer.
  • the polymer is less soluble in an aqueous medium than is the free form of the pharmaceutically active agent.
  • Another embodiment provides a polymer comprising the repeat unit:
  • L 1 , L 2 , and L 3 can be the same or different, and each are linking groups capable of covalently bonding to at least one of Di, D 2 , and BP,
  • Di is a chemical moiety that upon degradation of the polymer, forms a first pharmaceutically active agent
  • D 2 is a chemical moiety that upon degradation of the polymer, forms a second pharmaceutically active agent
  • BP is a biodegradable polymer.
  • the polymer is less soluble in an aqueous medium than is the free form of any of the pharmaceutically active agents.
  • compositions comprising a biodegradable polymer linked to a chemical moiety through a covalent bond, wherein the chemical moiety forms a pharmaceutically active agent upon degradation of the covalent bond, and wherein the polymer has a Tg greater than 37°C.
  • Tg is greater than 40°C, greater than 50°C or even greater than 6O°C.
  • Another embodiment provides a polymeric material comprising: a first biodegradable polymer portion comprising a chemical moiety of a pharmaceutically active agent bonded to a spacer group to form a backbone of the first polymer portion; a second biodegradable polymer portion bonded to the first polymer portion; wherein the pharmaceutically active agent is bonded to the spacer group via a linkage that is naturally hydrolysable in an in vivo environment, the polymeric material being less soluble in vivo than the free form of the pharmaceutically active agent is soluble in vivo.
  • the second polymer portion comprises one or more of polyglycolides, polylactides, polycaprolactones, polydioxanones, poly(lactide-co-glycolide), polyhydroxybutyrate, polyhydroxyvalerate, polyphosphoesters, polyphosphoester-urethane, polyamino acids, polycyanoacrylates, poly(trimethylene carbonate), fibrin, fibrinogen, cellulose, starch, collagen, and blends and copolymers of all of the foregoing.
  • Another embodiment provides a polymeric material comprising: a first biodegradable polymer portion comprising the repeat unit: [ L 3 -D 1 -L 1 -D 2 -L 2 -]- wherein:
  • L 1 , L 2 , and L 3 can be the same or different, and each are spacer groups capable of covalently bonding to at least one of D 1 , D 2 via a linkage that is naturally hydrolysable in vivo;
  • D 1 is a first chemical moiety that upon hydrolysis of the first polymer portion forms a first pharmaceutically active agent
  • D 2 is a second chemical moiety that upon hydrolysis of the first polymer portion forms a second pharmaceutically active agent; the polymer material further comprising a second biodegradable polymer portion bonded to the first polymer portion.
  • the polymeric material is less soluble in vivo than the free form of the first and second pharmaceutically active agents are soluble in vivo.
  • Another embodiment provides a polymeric material comprising: a first biodegradable polymer portion comprising the repeat unit: [L 4 -D 3 -L 3 -D 1 -L 1 -D 2 -L 2 -]- wherein:
  • L 1 , L 2 , L 3 and L 4 can be the same or different, and each are spacer groups capable of covalently bonding to at least one of D 1 , D 2, D 3 via a linkage that is naturally hydrolysable in vivo;
  • D 1 is a first chemical moiety that upon hydrolysis of the first polymer portion forms a first pharmaceutically active agent
  • D 2 is a second chemical moiety that upon hydrolysis of the first polymer portion forms a second pharmaceutically active agent
  • D 3 is a third chemical moiety that upon hydrolysis of the first polymer portion forms a third pharmaceutically active agent; the polymer material further comprising a second biodegradable polymer portion bonded to the first polymer portion.
  • the polymeric material is less soluble in vivo than the free form of the first, second and third pharmaceutically active agents are soluble in vivo.
  • compositions for coating at least a portion of a medical device comprising a polymer comprising at least two repeat units, each repeat unit comprising a chemical moiety covalently bonded to least one hydrolysable linking group wherein, the chemical moiety forms a pharmaceutically active agent upon hydrolysis of the covalent bond, and the composition (e.g., the polymer) has reduced solubility in an aqueous medium than the free form of the pharmaceutically active agent.
  • the hydrolysable linking group is selected from anhydride, ester, carbonate, and amide groups.
  • the pharmaceutically active agent is selected from anti-proliferative and anti-neoplastic agents.
  • the pharmaceutically active agent is selected from taxanes, limus derivatives, and non-steroidal anti-inflammatory agents.
  • the pharmaceutically active agent is selected from paclitaxel, sirolimus, everolimus, and biolimus.
  • the aqueous medium is selected from a physiological medium.
  • the physiological medium is selected from serum, bile, urine and extra-cellular fluid.
  • the linking groups are present in an amount ranging from 5% to 50% by weight relative to the total weight of the composition.
  • the pharmaceutically active agent is present in a dose density ranging from 0.1 to 4 ⁇ g/mm 2 .
  • the polymer has a Tg greater than 50°C.
  • the polymer has a Tg greater than 60°C.
  • each of the at least two repeat units comprises at least one polymer.
  • the at least one polymer is a biodegradable polymer.
  • the at least one polymer comprises D 1 L-PLA.
  • One embodiment provides a medical device having coated on at least a portion thereof the at least one coating comprising a composition, the composition comprising a polymer comprising at least two repeat units, each repeat unit comprising a chemical moiety covalently bonded to least one hydrolysable linking group wherein, the chemical moiety forms a pharmaceutically active agent upon hydrolysis of the covalent bond, and the composition (e.g., the polymer) has reduced solubility in an aqueous medium than the free form of the pharmaceutically active agent.
  • the at least one coating directly contacts the device.
  • the device is implantable into a mammalian lumen.
  • the device is a stent.
  • the stent is either balloon expandable or self-expanding.
  • the composition is coated on the stent to form a conformal coating around all surfaces of the stent.
  • the composition is coated only on the abluminal surface of the stent. In one embodiment, the composition is coated only on the abluminal surface of the stent and the composition resides partially or completely within micro-reservoirs or pores in the stent surface.
  • the device is selected from pacemaker leads, valve replacement and repair devices, vena cava filters, and embolic coils and beads.
  • the device is an angioplasty balloon having coated thereon the coating comprising the composition, wherein the balloon is used to deliver the composition to an endoluminal surface.
  • composition comprising at least two repeat units, each repeat unit comprising:
  • L 1 is a hydrolysable linking group
  • D 1 is a chemical moiety that upon degradation of covalent bonds binding it to the linking group, forms a pharmaceutically active agent.
  • the covalent bonds are selected from anhydride, ester, azo, and carbonate linkages.
  • the composition is a polymer having at least 10 of the repeat units.
  • each repeat unit has the formula:
  • BP is a biodegradable polymer
  • BP is chosen from PGLA and D 1 L-PLA.
  • a medical device such as an implantable medical device, having at least one coating covering at least a portion of the device, the at least one coating including a composition comprising a polymer with a repeat unit comprising the formula:
  • Another embodiment provides a polymer comprising the repeat unit:
  • L 1 and L 2 can be the same or different, and each are linking groups capable of covalently bonding to at least one of D 1 ,
  • D 1 is a chemical moiety that upon degradation of the polymer, forms a pharmaceutically active agent.
  • Another embodiment provides a composition comprising a biodegradable polymer linked to a chemical moiety through at least one covalent bond, wherein the chemical moiety forms a pharmaceutically active agent upon degradation of the covalent bond, and wherein the polymer has a Tg greater than 50°C.
  • Another embodiment provides the composition applied to at least a portion of a surface of a medical device, such as an implantable medical device.
  • compositions applied to the surface of a medical device comprising a prodrug of an antiproliferative active agent , wherein the prodrug comprises: an active antiproliferative agent [D] covalently bonded to, a hydrolysable linker group [H] covalently bonded to, a chemical moiety [C] of sufficient size and hydrophobicity to reduce the aqueous solubility of the composition to below that of the antiproliferative agent in free form.
  • [C] is a polymer with a molecular weight greater than 1 ,000 Da.
  • [C] is a polymer with a molecular weight greater than 10,000 Da.
  • [C] is a polymer comprising at least one monomeric unit selected from lactic acid, glycolic acid, caprolactone, lactide, glycolide, and thmethyl carbonate.
  • [C] is a polymer comprising long chain aliphatic hydrocarbons.
  • [C] is a polymer comprising aliphatic hydrocarbon chains of at least 6 carbon atoms.
  • [C] is a polymer comprising aliphatic hydrocarbon chains of at least 12 carbon atoms.
  • compositions comprising a biodegradable polymer, the biodegradable polymer being linked to a chemical moiety through a covalent bond, wherein, the chemical moiety forms a pharmaceutically active agent upon degradation of the covalent bond, the composition (e.g., the polymer) is less soluble in an aqueous medium than the free form of the pharmaceutically active agent, and the polymer has a Tg greater than 50°C.
  • FIG. 1 is a schematic showing a paclitaxel polymer via a covalent linking group
  • FIG. 2 is a schematic of a multi-layered coating containing different pharmaceutically active agents.
  • One embodiment provides a prodrug for at least one coating covering all or a portion of an implantable medical device.
  • a composition comprising a biodegradable polymer, the biodegradable polymer being linked to a chemical moiety through a covalent bond, wherein, the chemical moiety forms a pharmaceutically active agent upon degradation of the covalent bond.
  • the chemical moiety Upon degradation of the covalent bond, the chemical moiety forms a pharmaceutically active agent in its free form.
  • the "free form" of the pharmaceutically active agent can refer to the neutral compound, or salts thereof, e.g., the isolable or stable form of the agent.
  • the present invention relates to those compositions (comprising the chemical moiety) having a lower solubility in aqueous media (or in physiological media), than the free form of the pharmaceutically active agent.
  • a coating comprising a drug in a form affording it reduced solubility can provide a lesser probability of the drug being inadvertently eliminated by dissolution (or partial dissolution) prior to its reaching the target site.
  • the composition e.g., the polymer
  • the composition can be tailored to be more soluble in an aqueous medium than the free form of the pharmaceutically active agent.
  • the polymer has a Tg greater than 37°C, such as a Tg greater than 40°C or a Tg greater than 50°C.
  • a product of the degradation or hydrolysis is the pharmaceutically active agent, e.g., the free form of the agent.
  • the pharmaceutically active agent has a different structure than the free form of the pharmaceutically active agent but is the true active species that treats the disease or condition, e.g., the form of the agent in vivo.
  • the biodegradable polymer is linked to the chemical moiety. In one embodiment, the biodegradable polymer is linked to a pendant chemical moiety. In another embodiment, a "biodegradable polymer linked to a chemical moiety" refers to a chemical moiety incorporated in the backbone of the biodegradable polymer. In one embodiment, it is the biodegradable polymer that reduces the solubility of the agent.
  • the degradation of the covalent bond occurs via hydrolysis.
  • the hydrolysis can involve a direct reaction with an aqueous medium, or can be catalyzed chemically or enzymatically.
  • Aqueous medium refers to water, aqueous solutions, physiological media or biological fluids (e.g., body fluids), and other pharmaceutically acceptable media.
  • Suitable hydrolysable covalent bonds include those forming esters, amides, urethanes, carbamates, carbonates, azo linkages, anhydrides, thioesters, and combinations thereof.
  • the polymer i.e., the polymer containing the covalently linked chemical moiety
  • the polymer containing the covalently linked chemical moiety is biodegradable.
  • Biodegradable polymer refers to a polymer capable of hydrolyzing or otherwise degrading in an aqueous medium, as opposed to being soluble in an aqueous medium without degradation.
  • the resulting product(s) of biodegradation is soluble in the resulting body fluid or, if insoluble, can be suspended in a body fluid and transported away from the implantation site without clogging the flow of the body fluid.
  • the body fluid can be any fluid in the body of a mammal including, but not limited to, blood, serum, urine, saliva, lymph, plasma, gastric, biliary, or intestinal fluids, seminal fluids, and mucosal fluids, humors, and extracellular fluids.
  • the biodegradable polymer is soluble, degradable as defined above, or is an aggregate of soluble and/or degradable matehal(s) with insoluble matehal(s) such that, with the resorption of the soluble and/or degradable materials, the residual insoluble materials are of sufficiently fine size such that they can be suspended in a body fluid and transported away from the implantation site without clogging the flow of the body fluid.
  • the degraded compounds can be eliminated from the body either by excretion in perspiration, urine or feces, or dissolved, degraded, corroded or otherwise metabolized into soluble components that are then excreted from the body.
  • the biodegradable polymer imparts at least one mechanical property to the composition, such as adhesion, mechanical integrity, and coating properties. In one embodiment, the biodegradable polymer imparts at least one chemical property, such as chemical stability or reduced solubility in an aqueous medium.
  • any of the polymers disclosed herein has a Tg of greater than 37°C. In another embodiment, the Tg is greater than 40°C, greater than 50°C, or even greater than 60°C.
  • the biodegradable polymers are degraded through cleavage of functional groups such as esters, anhydrides, carbonates, thioesters, orthoesters, glycosidic bonds, phosphate esters, and amides. Suitable biodegradable polymers include those in the FDA GRAS (Generally Regarded As Safe) list, the disclosure of which is incorporated herein by reference.
  • biodegradable polymers include polyglycolides, polylactides (e.g., poly-l- lactide (PLLA)), polycaprolactones, polydioxanones, poly(lactide-co-glycolide) (PLGA), polyhydroxybutyrate, polyhydroxyvalerate, polyphosphoesters, polyphosphoester-urethane, polyamino acids, polycyanoacrylates, poly(thmethylene carbonate), biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen, and blends and copolymers thereof.
  • polylactides e.g., poly-l- lactide (PLLA)
  • polycaprolactones e.g., polydioxanones
  • poly(lactide-co-glycolide) (PLGA) polyhydroxybutyrate
  • polyhydroxyvalerate polyphosphoesters
  • polyphosphoester-urethane polyamino acids
  • polycyanoacrylates poly(thmethylene carbonate)
  • the biodegradable polymer is present in the composition in an amount ranging from 25% to 99% by weight relative to the total weight of the composition, such as an amount ranging from 25% to 95%, from 40% to 99%, or ranging from 40% to 95%.
  • the biodegradable polymer comprises PLA in an amount ranging from 15% to 100% by weight relative to the total weight of the biodegradable polymer.
  • the biodegradable polymer comprises a blend of polymers.
  • An exemplary blend is PLGA and D 1 L-PLA.
  • the biodegradable polymer comprises a blend of 15-85% PLGA, by weight relative to the total weight of the biodegradable polymer, with the remainder PLA.
  • the "chemical moiety” is a fragment of a pharmaceutically active agent.
  • the portion of the agent that is covalently bonded is the chemical moiety of the agent.
  • a biodegradable polymer "linked to a chemical moiety through a covalent bond” can refer to one or more covalent bonds.
  • the chemical moiety is linked directly to the polymer via one or more covalent bonds. "Linked directly” as used herein refers to the product of a reaction between the polymer and the pharmaceutically active agent, where the linking atom originates from the starting materials.
  • the chemical moiety is linked to the biodegradable polymer through covalent bond(s) to a linking group (comprising one or more molecules) or spacer that is covalently bonded to the polymer.
  • the linking group comes from an external reagent and does not originate from either the polymer or the pharmaceutically active agent.
  • Suitable linking groups bind the biodegradable polymer to the chemical moiety through covalent bonds, such as those covalent linkages described herein, e.g., ester, amide, carbamate, carbonate, azo, anhydride, and thioester linkages.
  • Other methods for covalently incorporating pharmaceuticals are provided in Qiu et al., "Polymer Architecture and Drug Delivery," Pharmaceutical Research, Vol. 23, No. 1 , pp. 1 -30 (2006), the disclosure of which is incorporated herein by reference.
  • FIG. 1 shows a schematic of a chemical moiety covalently linked to a biodegradable polymer.
  • the chemical moiety of FIG. 1 is paclitaxel (PAC), shown below:
  • PAC paclitaxel
  • a linking group containing two carbonyl chloride functional groups (acyl chlorides if L is, e.g., an alkyl group), is reacted with a hydroxyl group of paclitaxel in the presence of triethylamine (TEA).
  • TAA triethylamine
  • a polymer e.g., a biodegradable polymer
  • the L is a biodegradable polymer, resulting in the paclitaxel being directly bonded to the polymer.
  • the paclitaxel is bonded to the polymer via a series of carbonate/ester linkages, and other linkages such as anhydride, carbamate, etc., depending on the linking group and polymers.
  • compositions for coating at least a portion of a medical device comprising at least two repeat units, each repeat unit comprising a chemical moiety covalently bonded to least one hydrolysable linking group wherein, the chemical moiety forms a pharmaceutically active agent upon hydrolysis of the covalent bond.
  • the composition e.g., the polymer
  • the composition e.g., the polymer
  • the polymer has a Tg greater than 37°C, such as a Tg greater than 40°C, a Tg greater than 50°C, or a Tg greater than 60°C.
  • a "repeat unit comprising” refers to a composition that can have additional linking groups and species other than the repeat unit listed herein.
  • more than one pharmaceutically active agent other than the agent covalently bonded can be incorporated in the polymer.
  • the additional agents can be either covalently bonded to the polymer or even admixed with the polymer, so long as at least one agent is covalently bonded to the polymer.
  • the linking group can impart mechanical properties and release kinetics for the selected therapeutic application.
  • the linking group is a divalent organic radical having a molecular weight ranging from 25 daltons to 400 daltons, e.g., a molecular weight ranging from 40 daltons to 200 daltons.
  • the linking group has a length ranging from 5 angstroms to 100 angstroms using standard bond lengths and angles, e.g., a length ranging from 10 angstroms to 50 angstroms.
  • the linking group may be biologically inactive, or may itself possess biological activity.
  • the linking group can also comprise other functional groups (including hydroxy groups, mercapto groups, amine groups, carboxylic acids, as well as others) that can be used to modify the properties of the polymer (e.g. for branching, for cross linking, for appending other molecules (e.g. another biologically active compound) to the polymer, for reducing the solubility of the polymer, or for effecting the biodisthbution of the polymer).
  • the linking group is: a (C 1 -C 6 )alkyl, e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, 3-pentyl, or hexyl;
  • (C 3 - C 6 )cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
  • (C 3 - C 6 )cycloalkyl(C 1 -C 6 )alkyl can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2- cyclopentylethyl, or 2-cyclohexylethyl;
  • (C 1 -C 6 )alkoxy can be methoxy,
  • the linking group is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 20 carbon atoms, wherein the chain is optionally substituted on carbon with one or more (e.g.
  • substituents selected from (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 1 - C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy.
  • the linking group is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 20 carbon atoms, wherein one or more (e.g. 1 , 2, 3, or 4) of the carbon atoms is optionally replaced by (-O-) or (-NR-).
  • the linking group is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 3 to 15 carbon atoms, wherein one or more (e.g. 1 , 2, 3, or 4) of the carbon atoms is optionally replaced by (-O-) or NR-), and wherein the chain is optionally substituted on carbon with one or more (e.g.
  • substituents selected from (Cr C 6 )alkoxy, (C3-C6)cycloalkyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 - C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy.
  • the linking group is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 3 to 15 carbon atoms, wherein one or more (e.g. 1 , 2, 3, or 4) of the carbon atoms is optionally replaced by (-O-) or (-NR-).
  • the linking group is selected from amino acids and peptides.
  • the linking group is present in an amount ranging from 5% to 50% by weight relative to the total weight of the composition.
  • Exemplary pharmaceutically active agents include antiproliferative agents (e.g., those active against smooth muscle cells), anti-inflammatory agents, and healing promoters.
  • Exemplary antiproliferative agents include paclitaxel, sirolimus, everolimus, biolimus, zotarolimus, AP23573 (a sirolimus analog), and other limus derivatives.
  • anti-inflammatory agents include non-steroidal agents (e.g., 3-amino-4-hydroxybutyric acid, aceclofenac, alminoprofen, bromfenac, bumadizon, carprofen, diclofenac, diflunisal, enfenamic acid, etodolac, fendosal, flufenamic acid, gentisic acid, meclofenamic acid, mefenamic acid, mesalamine, niflumic acid, olsalazine oxaceprol, S-adenosylmethionine, salicylic acid, salsalate, sulfasalazine, tolfenamic acid).
  • non-steroidal agents e.g., 3-amino-4-hydroxybutyric acid, aceclofenac, alminoprofen, bromfenac, bumadizon, carprofen, diclofenac, diflunisal,
  • Exemplary healing promoters include nitric oxide donors such as halofuganone, S-nitrosothiols, and glyceryl thnitrite 1 -[N-(3- aminopropyl)-N-(3-ammoniopropyl]diazen-1 -ium-1 ,2-diolate, 1 -[N-(2-aminoethyl)-N- (2-annnnonioethyl)annino]diazen-1 -iunn-1 ,2-diolate, as well as epidermal growth factor and other growth factors.
  • nitric oxide donors such as halofuganone, S-nitrosothiols, and glyceryl thnitrite 1 -[N-(3- aminopropyl)-N-(3-ammoniopropyl]diazen-1 -ium-1 ,2-diolate, 1 -[N-(2-aminoethyl)
  • exemplary pharmaceutically active agents include analgesics, anesthetics, anti acne agents, antibiotics, synthetic antibacterial agents, anticholinergics, anticoagulants, antidyskinetics, antifibrotics, antifungal agents, antiglaucoma agents, anti-inflammatory agents, antineoplastics, antiosteoporotics, antipagetics, anti-Parkinson's agents, antisporatics, antipyretics, antiseptics/disinfectants, antithrombotics, bone resorption inhibitors, calcium regulators, keratolytics, sclerosing agents and ultraviolet screening agents.
  • exemplary antithrombotics and anticoagulants include aspirin and plavix.
  • the pharmaceutically active agent is a drug useful for treating diseases and conditions associated with restenosis, e.g., antithrombotics, anticoagulants, antiplatelet agents, thrombolytics, antiproliferatives, antiinflammatories, antimitotic, antimicrobial, agents that inhibit restenosis, smooth muscle cell inhibitors, antibiotics, fibrinolytic, immunosuppressive, and anti-antigenic agents.
  • a drug useful for treating diseases and conditions associated with restenosis e.g., antithrombotics, anticoagulants, antiplatelet agents, thrombolytics, antiproliferatives, antiinflammatories, antimitotic, antimicrobial, agents that inhibit restenosis, smooth muscle cell inhibitors, antibiotics, fibrinolytic, immunosuppressive, and anti-antigenic agents.
  • anti-bacterial compounds suitable for use in the present invention include, but are not limited to, 4-sulfanilamidosalicylic acid, acediasulfone, amfenac, amoxicillin, ampicillin, apalcillin, apicycline, aspoxicillin, aztreonam, bambermycin(s), biapenem, carbenicillin, carumonam, cefadroxil, cefamandole, cefatrizine, cefbuperazone, cefclidin, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefinenoxime, cefminox, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotetan, cefotiam, cefozopran, cefpimizole, cefpiramide, cefpirome, cefprozil, cefroxadine, ceft
  • anti-neoplastic compounds suitable for use in the present invention include, but are not limited to 6-diazo-5-oxo-L-norleucine, azaserine, carzinophillin A, denoptehn, edatrexate, eflomithine, melphalan, methotrexate, mycophenolic acid, podophyllinic acid 2-ethylhydrazide, pteroptehn, streptonigrin, Tomudex.RTM.
  • anti-thrombotic compounds for use in the present invention include, but are not limited to, argatroban, iloprost, lamifiban, taprostene, and tirofiban.
  • immunosuppressive compounds suitable for use in the present invention include, but are not limited to bucillamine, mycophenolic acid, procodazole, romurtide, and ubenimex.
  • Dosages of the pharmaceutically active agent may be determined by means known in the art. Typically, the dosage is dependent upon the particular drug employed and medical condition being treated to achieve a therapeutic result. In one embodiment, the amount of drug represents about 0.001 percent to about seventy percent of the total coating weight, or about 0.01 percent to about sixty percent of the total coating weight. In one embodiment, the weight percent of the therapeutic agents in the carrier or polymer coating is 1 % to 50%, 2% to 45%, 5% to 40%, or 10% to 25% by weight relative to the total coating weight. In another embodiment, it is possible that the drug may represent as little as 0.0001 percent to the total coating weight. In another embodiment, the dosage is determined per coated surface area of the device.
  • the dose density may range from 0.05 to 10 ⁇ g/mm 2 , such as a dose-density ranging from 0.05 to 1.0 ⁇ g/mm 2 , or ranging from 0.1 to 4 ⁇ g/mm 2 , or ranging from 0.2 to 4 ⁇ g/mm 2 .
  • the device delivers the agent over a selected period of time, such as days, weeks or months, e.g., such as a period of at least one week, at least two weeks, at least one month, at least six months, or at least one year.
  • a selected period of time such as days, weeks or months, e.g., such as a period of at least one week, at least two weeks, at least one month, at least six months, or at least one year.
  • the number average molecular weight of the polymer is 20,000 Da or less, such as a number average molecular weight of 10,000 Da or less, or 5,000 Da or less. In one embodiment, the number average molecular weight of the polymer ranges from 5,000 daltons to 100,000 daltons. In another embodiment, the number average molecular weight of the polymer is 25,000 Da or less. In yet another embodiment, the number average molecular weight of the polymer ranges from 25,000 daltons to 100,000 daltons.
  • Another embodiment provides a polymeric material comprising: a first biodegradable polymer portion comprising a chemical moiety of a pharmaceutically active agent bonded to a spacer group to form a backbone of the first polymer portion; a second biodegradable polymer portion bonded to the first polymer portion; wherein the pharmaceutically active agent is bonded to the spacer group via a linkage that is naturally hydrolysable in an in vivo environment, the polymeric material being less soluble in vivo than the free form of the pharmaceutically active agent is soluble in vivo.
  • the at least one pharmaceutically active agent is hydrophobic or amphipathic (e.g., paclitaxel).
  • hydrophobic agents may have some solubility in water, generally a hydrophobic agent generally dissolves more readily in oils or non-polar solvents than in water or polar solvents.
  • the agent is hydrophilic, e.g., dissolves more readily in water or polar solvents than in oils or non-polar solvents.
  • composition comprises a polymer comprising the repeat unit:
  • L 1 , L 2 , and L 3 can be the same or different and are linking groups
  • D 1 is a chemical moiety that upon degradation of covalent bonds binding it to a linking group and BP, forms an antiproliferative pharmaceutically active agent
  • D 2 is a chemical moiety that upon degradation of covalent bonds binding it to linking groups, forms an anti-inflammatory agent
  • D 3 is a chemical moiety that upon degradation of covalent bonds binding it to linking groups, forms a healing promoter
  • BP is a biodegradable polymer, such as the polymers disclosed herein.
  • the polymer is less soluble in an aqueous medium (e.g., a physiological medium) than is the free form of any of the pharmaceutically active agents Di, D 2 , and D 3 .
  • an aqueous medium e.g., a physiological medium
  • various drugs are incorporated in the polymer to impart different therapeutic effects.
  • the choice of L 1 , L 2 , L 3 , and the biodegradable polymer can allow control of release profile and kinetics of pharmaceutically active agents from the medical device.
  • the release profile and kinetics can be controlled by the hydrolysis rates and chemistry of the various hydrolytic linkages.
  • the period of time of drug delivery and drug dosage can be controlled to substantially prevent undesirable burst release.
  • the linking groups and biodegradable polymer can be chosen to provide desirable mechanical properties.
  • a "polymer comprising the repeat unit” can have additional linking groups and repeat units other than the repeat unit listed herein.
  • pharmaceutically active agents in addition to D 1 , D 2 , and D 3 can also be present in the composition, e.g., any other agents useful for treating vascular injury, e.g., restenosis.
  • pharmaceutically active agents in addition to D1 , D 2 , and D 3 can be incorporated in the polymer, e.g., either covalently linked to the polymer or admixed with the polymer.
  • the composition comprises a polymer comprising the repeat unit:
  • BP is derived from a biodegradable polymer
  • D is a chemical moiety that releases a pharmaceutically active agent upon degradation of the covalent bond to BP, e.g., upon hydrolysis of covalent bonds binding it to BP.
  • D is a chemical moiety that releases rapamycin and/or paclitaxel.
  • BP is derived from one or more polymers selected from PLLA, PDLA, PDLLA, PGA, PLGA, polycaprolactone, polydioxinone, polymers prepared from mono and/or bis-carboxymethyl-polyethyleneglycol, and poly amino acids prepared from one or more monomers such as glycine, alanine, leucine, isoleucine, norleucine, valine, norvaline, methionine, phenylalanine, and tryptophan.
  • the composition comprises a polymer comprising the repeat unit:
  • L is a linker derived from one or more molecules selected from diacids, diols, diamines, hydroxyacids, amino acids, and other difunctional molecules that can be bonded to D and to BP;
  • D is a chemical moiety that releases a pharmaceutically active agent upon degradation of the covalent bond, e.g., upon hydrolysis of covalent bonds binding it to L and BP;
  • BP is derived from a biodegradable polymer that can be bonded to L and D; and n is either 1 , 2, 1 -5, 1 -20, 1 -50, 1 -100 or 1 -500.
  • L is derived from one or more molecules selected from carbonic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, pimelic acid, adipic acid, and sebacic acid.
  • BP is derived from one or more polymers selected from PLLA, PDLA, PDLLA, PGA, PLGA, polycaprolactone, polydioxinone, polymers prepared from mono and/or bis-carboxymethyl- polyethyleneglycol, and poly amino acids prepared from one or more monomers selected from glycine, alanine, leucine, isoleucine, norleucine, valine, norvaline, methionine, phenylalanine, and tryptophan.
  • D is a chemical moiety that releases rapamycin and/or paclitaxel.
  • the composition comprises a polymer comprising the repeat unit:
  • L is a linker derived from one or molecules selected from triacids, dihydroxy acids, hydroxy diacids, amino diacids, diamino acids, and other trifunctional molecules that can be bonded to D and to BP;
  • D is a chemical moiety that releases a pharmaceutically active agent upon degradation of the covalent bond, e.g., upon hydrolysis of covalent bonds binding it to L;
  • BP is derived from a biodegradable polymer that can be bonded to L; and n is either 1 , 2, 1 -5, 1 -20, 1 -50, 1 -100 or 1 -500.
  • L is derived from one or more of glutamic acid, aspartic acid and/or glyceric acid
  • D is a chemical moiety that releases rapamycin or paclitaxel
  • BP is derived from one or more of PLLA, PDLA, PDLLA, PGA, PLGA, polycaprolactone, polydioxinone, mono-carboxyethyl-polyethyleneglycol, and/or poly amino acids prepared from one or more monomers selected from glycine, alanine, leucine, isoleucine, norleucine, valine, norvaline, methionine, phenylalanine, and tryptophan.
  • the composition comprises a polymer comprising the repeat unit:
  • L is a linker derived from one or more molecules selected from triacids, dihydroxy acids, hydroxy diacids, amino diacids, diamino acids, and other trifunctional molecules that can be bonded to D and to BP;
  • D is a chemical moiety that releases a pharmaceutically active agent upon hydrolysis of covalent bonds binding it to L and BP;
  • BP is derived from a biodegradable polymer that can be bonded to L and D; and n is either 1 , 2, 1 -5, 1 -20, 1 -50, 1 -100, or 1 -500.
  • L is derived from 2-carboxyglutaric acid
  • D is a chemical moiety that releases rapamycin or paclitaxel
  • BP is derived from one or more of PLLA, PDLA, PDLLA, PGA, PLGA, polycaprolactone, polydioxinone, polymers prepared from mono and/or bis-carboxyethyl-polyethyleneglycol, and poly amino acids prepared from one or more monomers selected from glycine, alanine, leucine, isoleucine, norleucine, valine, norvaline, methionine, phenylalanine, and tryptophan.
  • L is derived from one or more of glutamic acid, aspartic acid or glyceric acid
  • D is a chemical moiety that releases rapamycin and/or paclitaxel
  • BP is derived from bis-carboxymethyl-polyethyleneglycol.
  • FIG. 2 is a schematic showing a multi-layered coating arrangement, where each of layers 1 , 2, and 3 contain either a unique pharmaceutically active agent, or if two or more layers contain the same agent, the agent is linked to the polymer via a different linking chemistry.
  • This arrangement allows control of the release profile of the agents and can provide control of the sequence of release of different pharmaceutically active agents.
  • each layer can be individually customized by choice of agents, linking chemistry, polymer structure, thickness, etc. for controlling the release profile and kinetics.
  • each layer contains a unique agent, e.g., Di, D 2 , and D 3 , as described herein, or any other agents useful for treating vascular injury, e.g., restenosis.
  • a unique agent e.g., Di, D 2 , and D 3 , as described herein, or any other agents useful for treating vascular injury, e.g., restenosis.
  • pharmaceutically active agents in addition to Di, D 2 , and D 3 can be incorporated in the polymer, e.g., either covalently linked to the polymer or admixed with the polymer.
  • the device treats narrowing or obstruction of a body passageway in a subject in need thereof.
  • the method comprises inserting the device into the passageway, the device comprising a generally tubular structure, the surface of the structure being coated with a composition disclosed herein, such that the passageway is expanded.
  • the body passageway may be selected from arteries, veins, lacrimal ducts, trachea, bronchi, bronchiole, nasal passages, sinuses, eustachian tubes, the external auditory canal, oral cavities, the esophagus, the stomach, the duodenum, the small intestine, the large intestine, biliary tracts, the ureter, the bladder, the urethra, the fallopian tubes, uterus, vagina, the vasdeferens, and the ventricular system.
  • the implantable devices disclosed herein are implanted in a subject in need thereof to achieve a therapeutic effect, e.g., therapeutic treatment and/or prophylactic/preventative measures.
  • a therapeutic effect e.g., therapeutic treatment and/or prophylactic/preventative measures.
  • Those in need of treatment may include individuals already having a particular medical disease as well as those at risk for the disease (e.g., those who are likely to ultimately acquire the disorder).
  • a therapeutic method can also result in the prevention or amelioration of symptoms, or an otherwise desired biological outcome, and may be evaluated by improved clinical signs, delayed onset of disease, reduced/elevated levels of lymphocytes and/or antibodies.
  • the method is used for treating at least one disease or condition associated with vascular injury or angioplasty, e.g., one or more of atherosclerosis, restenosis, neointima, neointimal hyperplasia and thrombosis.
  • vascular injury or angioplasty e.g., one or more of atherosclerosis, restenosis, neointima, neointimal hyperplasia and thrombosis.
  • Exemplary devices include sutures, staples, anastomosis devices, vertebral disks, bone pins, suture anchors, hemostatic barriers, clamps, screws, plates, clips, vascular implants, urological implants, tissue adhesives and sealants, tissue scaffolds, bone substitutes, intraluminal devices, and vascular supports.
  • the device can be a cardiovascular device, such as venous catheters, venous ports, tunneled venous catheters, chronic infusion lines or ports, including hepatic artery infusion catheters, pacemakers and pace maker leads, and implantable defibrillators.
  • the device can be a neurologic/neurosurgical device such as ventricular peritoneal shunts, ventricular atrial shunts, nerve stimulator devices, dural patches and implants to prevent epidural fibrosis post- laminectomy, and devices for continuous subarachnoid infusions.
  • the device can be a gastrointestinal device, such as chronic indwelling catheters, feeding tubes, portosystemic shunts, shunts for ascites, peritoneal implants for drug delivery, peritoneal dialysis catheters, and suspensions or solid implants to prevent surgical adhesions.
  • the device can be a genitourinary device, such as uterine implants, including intrauterine devices (IUDs) and devices to prevent endometrial hyperplasia, fallopian tubal implants, including reversible sterilization devices, fallopian tubal stents, artificial sphincters and periurethral implants for incontinence, ureteric stents, chronic indwelling catheters, bladder augmentations, or wraps or splints for vasovasostomy, central venous catheters.
  • IUDs intrauterine devices
  • devices to prevent endometrial hyperplasia include reversible sterilization devices, fallopian tubal stents, artificial sphincters and periurethral implants for incontinence, ureteric stents, chronic indwelling catheters, bladder augmentations, or wraps or splints for vasovasostomy, central venous catheters.
  • IUDs intrauterine devices
  • Other exemplary devices include prosthetic heart valves, vascular grafts ophthalmologic implants (e.g., multino implants and other implants for neovascular glaucoma, drug eluting contact lenses for pterygiums, splints for failed dacrocystalrhinostomy, drug eluting contact lenses for corneal neovascularity, implants for diabetic retinopathy, drug eluting contact lenses for high risk corneal transplants), otolaryngology devices (e.g., ossicular implants, Eustachian tube splints or stents for glue ear or chronic otitis as an alternative to transtempanic drains), plastic surgery implants (e.g., breast implants or chin implants), and catheter cuffs and orthopedic implants (e.g., cemented orthopedic prostheses).
  • vascular grafts ophthalmologic implants e.g., multino implants and other implants for neovascular gla
  • the device is selected from pacemaker leads, valve replacement and repair devices, vena cava filters, and embolic coils and beads.
  • a stent such as a stent comprising a generally tubular structure.
  • a stent is commonly used as a tubular structure disposed inside the lumen of a duct to relieve an obstruction.
  • the stent is either balloon expandable or self-expanding.
  • stents are inserted into the lumen in a non-expanded form and are then expanded autonomously, or with the aid of a second device in situ.
  • a typical method of expansion occurs through the use of a catheter-mounted angioplasty balloon which is inflated within the stenosed vessel or body passageway in order to shear and disrupt the obstructions associated with the wall components of the vessel and to obtain an enlarged lumen.
  • An exemplary stent is a stent for treating narrowing or obstruction of a body passageway in a human or animal in need thereof.
  • Body passageway refers to any of number of passageways, tubes, pipes, tracts, canals, sinuses or conduits which have an inner lumen and allow the flow of materials within the body.
  • body passageways include arteries and veins, lacrimal ducts, the trachea, bronchi, bronchiole, nasal passages (including the sinuses) and other airways, eustachian tubes, the external auditory canal, oral cavities, the esophagus, the stomach, the duodenum, the small intestine, the large intestine, biliary tracts, the ureter, the bladder, the urethra, the fallopian tubes, uterus, vagina and other passageways of the female reproductive tract, the vasdeferens and other passageways of the male reproductive tract, and the ventricular system (cerebrospinal fluid) of the brain and the spinal cord.
  • Exemplary devices of the invention are for these above-mentioned body passageways, such as stents, e.g., vascular stents.
  • stents e.g., vascular stents.
  • vascular stents There is a multiplicity of different vascular stents known in the art that may be utilized following percutaneous transluminal coronary angioplasty.
  • stents Any number of stents may be utilized in accordance with the present invention and the invention is not limited to the specific stents that are described in exemplary embodiments of the present invention. The skilled artisan will recognize that any number of stents may be utilized in connection with the present invention. In addition, as stated above, other medical devices may be utilized, such as e.g., orthopedic implants.
  • the composition is coated on the stent to form a conformal coating around all surfaces of the stent. In another embodiment, the composition is coated only on the abluminal surface of the stent. In one embodiment, the composition resides partially or completely within micro-reservoirs or pores in the stent surface.
  • the device is an angioplasty balloon having coated thereon the coating comprising the composition, wherein the balloon is used to deliver the composition to an endoluminal surface.
  • the devices of the invention may be coated partially or wholly with the above defined compositions in any manner known in the art, e.g., dipping, spraying, rolling, brushing, electrostatic plating or spinning, vapor deposition (e.g., physical or chemical), air spraying including atomized spray coating, and spray coating using an ultrasonic nozzle.
  • the compositions can be applied by these methods either as a solid (e.g., film or particles), a suspension, a solution, or as a vapor.
  • the device can be coated with a first substance (such as a hydrogel) that is capable of absorbing the composition.
  • the device can be constructed from a material comprising a polymer/drug composition.
  • Ampicillin, paclitaxel and rapamycine were obtained from Huei-Ho international Co LTDchina.
  • Dimethylformamide (DMF), pyridine, triethylamine, acetic anhydride, methylene chloride (anhydrous), and diethyl ether were purchased from Finar & SDfine chemical. All other fine chemicals and solvents were obtained from SDfine chemical HYD.
  • Triethylamine was dried over calcium hydride (CaC ⁇ ) and all other reagents were used with no further purification.
  • the white solid (Ampicillin-sebacic diacid, 1 ) that formed was isolated by vacuum filtration, washed with water (2x50ml_) and dried overnight under vacuum at room temperature. Ampicillin-sebacic Diacid (1). Yield: 70% (white powder).
  • Ampicillin-sebacic diacid (1) (1.2g, 1.38mnnol) was dissolved in CH 2 CI 2 (2OmL) and thethylamine (0.8mL, 6.52mmol).
  • Triphosgene (0.045g, 1.52mmol) dissolved in dichloromethane (5ml_) was added drop wise over 15 minutes to the stirring reaction mixture at 0 °C to afford a suspension.
  • the reaction was stirred for 2 h at 0 °C under nitrogen and poured over diethyl ether (5OmL).
  • the solid (polymer, 2) that formed was isolated by vacuum filtration, washed with acidic water (2x50mL) and dried overnight under vacuum at room temperature. Poly-ampicillin-sebacic (2).
  • Ampicillin (1.9g, 5.46mnnol) was added to DMF (25ml_) and pyridine (2.2ml_, 2.73mnnol) to a suspension.
  • Adipoyl-chloride (0.4mL, 2.73mnnol) dissolved in dimethylformannide (5mL) was added drop wise over 5 minutes to the stirring reaction mixture at 0°C to afford a clear solution.
  • the reaction was stirred for 2h at 0°C, poured over water (10OmL) and acidified to pH ⁇ 2 using 0.1 N hydrochloric acid solution while stirring.
  • the white solid (Ampicillin-adipic diacid,) that formed was isolated by vacuum filtration, washed with water (2x50ml_) and dried overnight under vacuum at room temperature. Ampicillin-adipic diacid. Yield: 50% (white powder).
  • Paclitaxel (0.2g, 0.23mmol) was dissolved in CH 2 CI 2 (2OmL) and triethylamine (0.13g, 0.93mnnol) to a suspension, sebacoyl-chlohde (0.56mL, 0.23mnnol) dissolved in CH 2 CI 2 (2OmL) was added drop wise over 15 minutes to the stirring reaction mixture at 0°C.
  • the reaction mixture was stirred for 3h at 0°C under nitrogen and poured over DCM (5OmL). Washed with acidic water (2x50mL) and dried over Na 2 SO 4 filtered, concentrated under vacuum and the crude compound was purified by pre-HPLC to afford Poly-paclitaxel-sebacoyl.
  • linker reagents such as triphosgene
  • sebacoyl chloride can be substituted for sebacoyl chloride to provide a carbonate-derived linker.
  • a mixture of triphosgene and sebacoyl chloride can be used as linker reagents to provide a linker of carbonate- and sebacoyl-derived linkers.
  • Paclitaxel (0.2g, 0.23mmol) was dissolved in CH2CI2 (2OmL) and triethylamine (0.13ml_, 0.93mmol) to a suspension.
  • Adipoyl-chloride (0.03ml_, 0.23mmol) dissolved in CH2CI2 (5ml_) was added drop wise over 15 minutes to the stirring reaction mixture at 0°C.
  • the reaction mixture was stirred for 2h at 0°C under nitrogen and poured over DCM (5OmL). Washed with acidic water (2x50mL) and dried over Na2SO4 filtered, concentrated under vacuum and the crude compound was purified by pre-HPLC to afford Poly-paclitaxel-adipic. Yield: 50% (white powder).
  • Rapamycin (0.2g, 0.22mmol) was dissolved in CH 2 CI 2 (2OmL) and triethylamine (0.12ml_, 10.87mnnol) to a suspension.
  • Adipoyl-chloride (0.03mL, 0.22mnnol) dissolved in CH 2 CI 2 (5ml_) was added drop wise over 15 minutes to the stirring reaction mixture at 0°C.

Abstract

Disclosed herein are coatings for implantable medical device. The coatings comprise a biodegradable polymer linked to a chemical moiety through a covalent bond, wherein the chemical moiety forms a pharmaceutically active agent upon degradation of the covalent bond.

Description

DRUG ELUTING MEDICAL DEVICE USING POLYMERIC THERAPEUTICS
RELATED APPLICATIONS
[01] This application claims the benefit of priority under 35 U. S. C. § 119(e) to U.S. Prov. App. No. 60/885,097, filed January 16, 2007, U.S. Prov. App. No. 60/885,105, filed January 16, 2007, U.S. Prov. App. No. 60/885,109, filed January 16, 2007, U.S. Prov. App. No. 60/885,112, filed January 16, 2007, U.S. Prov. App. No. 60/942,301 , filed June 6, 2007, and U.S. Prov. App. No. 60/942,309, filed June 6, 2007, and U.S. Prov. App. No.60/943,077, filed June 11 , 2007, the disclosures of which are incorporated herein by reference.
FIELD OF THE INVENTION
[02] The present invention relates to coatings for medical devices, such as implantable medical devices comprising biodegradable polymers that upon hydrolysis, form one or more pharmaceutically active agents.
BACKGROUND OF THE INVENTION
[03] Restenosis is a complex disease state that is being treated by drug eluting stents (DES). Currently, commercially available DES comprise a coated stent where the coating includes a single drug eluted from a polymeric carrier.
[04] For DES treatments, sustained delivery of the drug is generally desired. With a coating comprising a nonbiodegradable polymeric carrier, the mechanism for drug release into the bloodstream is diffusion of the drug through the polymer. Biodegradable polymers have been developed in stent coatings that ideally should reduce the dependency on diffusion and allow sustained drug delivery due to degradation of the polymer in vivo. However, in practice, even systems employing biodegradable polymers ultimately rely mainly on the diffusion mechanism as the polymer degradation rate is too slow for delivering an effective amount of drug to the bloodstream over the required time period.
[05] Accordingly, there remains a need to develop new coatings for implantable medical devices that allow sustained drug release. SUMMARY OF THE INVENTION
[06] One embodiment provides a composition comprising a biodegradable polymer, the biodegradable polymer being linked to a chemical moiety through a covalent bond, wherein, the chemical moiety forms a pharmaceutically active agent upon degradation of the covalent bond, and the composition is less soluble in an aqueous medium than the free form of the pharmaceutically active agent.
[07] In one embodiment, the polymer has a Tg greater than 37°C, e.g., greater than 40°C, greater than 50°C, or even greater than 60°C.
[08] In one embodiment, the covalent bond is hydrolytically degradable.
[09] In one embodiment, the composition is used for at least one coating for an implantable medical device, the at least one coating covering at least a portion of the device.
[10] In one embodiment, the biodegradable polymer comprises at least one monomeric unit selected from lactic acid, glycolic acid, caprolactone, lactide, glycolide, and thmethyl carbonate.
[11] Another embodiment provides implantable medical device having at least one coating covering at least a portion of the device, the at least one coating including a compound comprising a biodegradable polymer linked to a chemical moiety through a covalent bond, wherein the chemical moiety forms a pharmaceutically active agent upon degradation of the covalent bond, and wherein the compound has a Tg greater than 37°C, e.g., greater than 40°C, greater than 50°C, or even greater than 60°C.
[12] In one embodiment, the chemical moiety is linked to the biodegradable polymer via a linking group.
[13] In one embodiment, the covalent bond is selected from anhydride and ester bonds.
[14] In one embodiment, the chemical moiety is linked to the biodegradable polymer as a pendant group of the polymer chain.
[15] In one embodiment, the chemical moiety is a portion of the polymer backbone. [16] In one embodiment, the covalent bond is hydrolytically degradable.
[17] In one embodiment, the pharmaceutically active agent is selected from taxanes, limus derivatives, and non-steroidal anti-inflammatory agents.
[18] In one embodiment, the pharmaceutically active agent is selected from paclitaxel, sirolimus, everolimus, and biolimus.
[19] In one embodiment, wherein the pharmaceutically active agent is hydrophobic.
[20] In one embodiment, the compound is less soluble than the free form of the pharmaceutically active agent.
[21] In one embodiment, the biodegradable polymer is present in an amount ranging from 40% to 95% by weight relative to the total weight of the composition.
[22] In one embodiment, the pharmaceutically active agent is present in a dose density ranging from 0.05 to 10 μg/mm2.
[23] In one embodiment, the number average molecular weight of the polymer is 20,000 Da or less, such as a number average molecular weight of 10,000 Da or less, or 5,000 Da or less. In one embodiment, the number average molecular weight of the polymer ranges from 5,000 daltons to 100,000 daltons. In another embodiment, the number average molecular weight of the polymer is 25,000 Da or less. In yet another embodiment, the number average molecular weight of the polymer ranges from 25,000 daltons to 100,000 daltons.
[24] In one embodiment, the at least one coating comprises at least two coatings to provide a multi-layered structure.
[25] In one embodiment, the at least one coating comprises at least three coatings.
[26] In one embodiment, each of the at least three coatings provides a different chemical moiety that forms a different pharmaceutically active agent. In one embodiment, the composition in one of the at least three coatings comprises a chemical moiety that forms an antiproliferative pharmaceutically active agent. In one embodiment, the composition in one of the at least three coatings comprises a chemical moiety that forms an anti-inflammatory agent. In one embodiment, the composition in one of the at least three coatings comprises a chemical moiety that forms a healing promoter.
[27] In one embodiment, the at least one coating directly contacts the device.
[28] In one embodiment, an inner coating free of a pharmaceutically active agent that directly contacts the device, wherein the inner coating also directly contacts the at least one coating.
[29] In one embodiment, the device is implantable into a mammalian lumen. In one embodiment, the device is a stent. In one embodiment, the stent is either balloon expandable or self-expanding.
[30] In one embodiment, the composition is coated on the stent to form a conformal coating around all surfaces of the stent.
[31] In one embodiment, the composition is coated only on the abluminal surface of the stent. In one embodiment, the composition is coated only on the abluminal surface of the stent and the composition resides partially or completely within micro-reservoirs or pores in the stent surface.
[32] In one embodiment, the device is selected from pacemaker leads, valve replacement and repair devices, vena cava filters, and embolic coils and beads.
[33] In one embodiment, the device is an angioplasty balloon having coated thereon the coating comprising the composition, wherein the balloon is used to deliver the composition to an endoluminal surface.
[34] In one embodiment, the polymer has a Tg greater than 40°C. In one embodiment, the polymer has a Tg greater than 50°C, or greater than 60°C.
[35] In one embodiment, the biodegradable polymer is a blend comprising 15-85 weight percent PLGA relative to the total weight of the biodegradable polymer.
[36] In one embodiment, the blend further comprises D1L-PLA.
[37] In one embodiment, the polymer comprises D1L-PLA.
[38] Another embodiment provides a polymer comprising the repeat unit:
-[Di-Li-D2-L2-D3-L3-BP]- wherein: L1, L2, and L3 can be the same or different, and each are linking groups capable of covalently bonding to at least one of Di, D2, and BP,
Di is a chemical moiety that upon degradation of covalent bonds binding it to a linking group and BP, forms an antiproliferative pharmaceutically active agent,
D2 is a chemical moiety that upon degradation of covalent bonds binding it to linking group, forms an anti-inflammatory agent,
D3 is a chemical moiety that upon degradation of covalent bonds binding it to linking groups, forms a healing promoter, and
BP is a biodegradable polymer.
[39] In one embodiment, the polymer forms at least one coating covering at least a portion of an implantable medical device.
[40] In one embodiment, L1 together with D1 and D2, L2 together with together with D1 and D3, and L3 together with D3 and BP, form covalent bonds chosen from anhydride, ester, azo, and carbonate linkages.
[41] In one embodiment, BP is chosen from PGLA and D1L-PLA. [42] Another embodiment provides a polymer comprising the repeat unit:
-[D1-L1-BP]- wherein:
L1 is a linking group capable of covalently bonding to at least one of D1 and BP,
D1 is a chemical moiety that upon degradation of the polymer, forms a pharmaceutically active agent, and
BP is a biodegradable polymer.
[43] In one embodiment, the polymer is less soluble in an aqueous medium than is the free form of the pharmaceutically active agent.
[44] Another embodiment provides a polymer comprising the repeat unit:
-[L2-D1-L1- BP]- wherein:
L1 and L2 can be the same or different, and each are linking groups capable of covalently bonding to at least one of D1 and BP, D1 is a chemical moiety that upon degradation of the polymer, forms a pharmaceutically active agent, and
BP is a biodegradable polymer.
[45] In one embodiment, the polymer is less soluble in an aqueous medium than is the free form of the pharmaceutically active agent.
[46] Another embodiment provides a polymer comprising the repeat unit:
[L3-D1-L1-D2-L2- BP]- wherein:
L1, L2, and L3 can be the same or different, and each are linking groups capable of covalently bonding to at least one of Di, D2, and BP,
Di is a chemical moiety that upon degradation of the polymer, forms a first pharmaceutically active agent,
D2 is a chemical moiety that upon degradation of the polymer, forms a second pharmaceutically active agent, and
BP is a biodegradable polymer.
[47] In one embodiment, the polymer is less soluble in an aqueous medium than is the free form of any of the pharmaceutically active agents.
[48] Another embodiment provides a composition comprising a biodegradable polymer linked to a chemical moiety through a covalent bond, wherein the chemical moiety forms a pharmaceutically active agent upon degradation of the covalent bond, and wherein the polymer has a Tg greater than 37°C. In another embodiment, Tg is greater than 40°C, greater than 50°C or even greater than 6O°C. [49] Another embodiment provides a polymeric material comprising: a first biodegradable polymer portion comprising a chemical moiety of a pharmaceutically active agent bonded to a spacer group to form a backbone of the first polymer portion; a second biodegradable polymer portion bonded to the first polymer portion; wherein the pharmaceutically active agent is bonded to the spacer group via a linkage that is naturally hydrolysable in an in vivo environment, the polymeric material being less soluble in vivo than the free form of the pharmaceutically active agent is soluble in vivo. [50] In one embodiment, the second polymer portion comprises one or more of polyglycolides, polylactides, polycaprolactones, polydioxanones, poly(lactide-co-glycolide), polyhydroxybutyrate, polyhydroxyvalerate, polyphosphoesters, polyphosphoester-urethane, polyamino acids, polycyanoacrylates, poly(trimethylene carbonate), fibrin, fibrinogen, cellulose, starch, collagen, and blends and copolymers of all of the foregoing.
[51] Another embodiment provides a polymeric material comprising: a first biodegradable polymer portion comprising the repeat unit: [ L3-D1-L1-D2-L2-]- wherein:
L1, L2, and L3 can be the same or different, and each are spacer groups capable of covalently bonding to at least one of D1, D2 via a linkage that is naturally hydrolysable in vivo;
D1 is a first chemical moiety that upon hydrolysis of the first polymer portion forms a first pharmaceutically active agent;
D2 is a second chemical moiety that upon hydrolysis of the first polymer portion forms a second pharmaceutically active agent; the polymer material further comprising a second biodegradable polymer portion bonded to the first polymer portion.
[52] In one embodiment, the polymeric material is less soluble in vivo than the free form of the first and second pharmaceutically active agents are soluble in vivo.
[53] Another embodiment provides a polymeric material comprising: a first biodegradable polymer portion comprising the repeat unit: [L4-D3-L3-D1-L1-D2-L2-]- wherein:
L1, L2, L3 and L4 can be the same or different, and each are spacer groups capable of covalently bonding to at least one of D1, D2, D3 via a linkage that is naturally hydrolysable in vivo;
D1 is a first chemical moiety that upon hydrolysis of the first polymer portion forms a first pharmaceutically active agent; D2 is a second chemical moiety that upon hydrolysis of the first polymer portion forms a second pharmaceutically active agent;
D3 is a third chemical moiety that upon hydrolysis of the first polymer portion forms a third pharmaceutically active agent; the polymer material further comprising a second biodegradable polymer portion bonded to the first polymer portion.
[54] In one embodiment, the polymeric material is less soluble in vivo than the free form of the first, second and third pharmaceutically active agents are soluble in vivo.
[55] One embodiment provides a composition for coating at least a portion of a medical device, the composition comprising a polymer comprising at least two repeat units, each repeat unit comprising a chemical moiety covalently bonded to least one hydrolysable linking group wherein, the chemical moiety forms a pharmaceutically active agent upon hydrolysis of the covalent bond, and the composition (e.g., the polymer) has reduced solubility in an aqueous medium than the free form of the pharmaceutically active agent.
[56] In one embodiment, the hydrolysable linking group is selected from anhydride, ester, carbonate, and amide groups.
[57] In one embodiment, the pharmaceutically active agent is selected from anti-proliferative and anti-neoplastic agents.
[58] In one embodiment, the pharmaceutically active agent is selected from taxanes, limus derivatives, and non-steroidal anti-inflammatory agents.
[59] In one embodiment, the pharmaceutically active agent is selected from paclitaxel, sirolimus, everolimus, and biolimus.
[60] In one embodiment, the aqueous medium is selected from a physiological medium.
[61] In one embodiment, the physiological medium is selected from serum, bile, urine and extra-cellular fluid.
[62] In one embodiment, the linking groups are present in an amount ranging from 5% to 50% by weight relative to the total weight of the composition. [63] In one embodiment, the pharmaceutically active agent is present in a dose density ranging from 0.1 to 4 μg/mm2.
[64] In one embodiment, the polymer has a Tg greater than 50°C.
[65] In one embodiment, the polymer has a Tg greater than 60°C.
[66] In one embodiment, each of the at least two repeat units comprises at least one polymer. In one embodiment, the at least one polymer is a biodegradable polymer. In one embodiment, the at least one polymer comprises D1L-PLA.
[67] One embodiment provides a medical device having coated on at least a portion thereof the at least one coating comprising a composition, the composition comprising a polymer comprising at least two repeat units, each repeat unit comprising a chemical moiety covalently bonded to least one hydrolysable linking group wherein, the chemical moiety forms a pharmaceutically active agent upon hydrolysis of the covalent bond, and the composition (e.g., the polymer) has reduced solubility in an aqueous medium than the free form of the pharmaceutically active agent..
[68] In one embodiment, the at least one coating directly contacts the device.
[69] In one embodiment, the device is implantable into a mammalian lumen.
[70] In one embodiment, the device is a stent. In one embodiment, the stent is either balloon expandable or self-expanding.
[71] In one embodiment, the composition is coated on the stent to form a conformal coating around all surfaces of the stent.
[72] In one embodiment, the composition is coated only on the abluminal surface of the stent. In one embodiment, the composition is coated only on the abluminal surface of the stent and the composition resides partially or completely within micro-reservoirs or pores in the stent surface.
[73] In one embodiment, the device is selected from pacemaker leads, valve replacement and repair devices, vena cava filters, and embolic coils and beads. [74] In one embodiment, the device is an angioplasty balloon having coated thereon the coating comprising the composition, wherein the balloon is used to deliver the composition to an endoluminal surface.
[75] A composition comprising at least two repeat units, each repeat unit comprising:
-[D1-L1]- wherein:
L1 ,is a hydrolysable linking group, and
D1 is a chemical moiety that upon degradation of covalent bonds binding it to the linking group, forms a pharmaceutically active agent. [76] In one embodiment, the covalent bonds are selected from anhydride, ester, azo, and carbonate linkages.
[77] In one embodiment, the composition is a polymer having at least 10 of the repeat units.
[78] In one embodiment, each repeat unit has the formula:
-[D1-L1-BP]- wherein BP is a biodegradable polymer.
[79] In one embodiment, BP is chosen from PGLA and D1L-PLA. [80] Another embodiment provides a medical device, such as an implantable medical device, having at least one coating covering at least a portion of the device, the at least one coating including a composition comprising a polymer with a repeat unit comprising the formula:
-[D1-L1-BP]- wherein BP is a biodegradable polymer. [81] Another embodiment provides a polymer comprising the repeat unit:
-[ L2-D1-L1-D1]- wherein:
L1 and L2 can be the same or different, and each are linking groups capable of covalently bonding to at least one of D1 ,
D1 is a chemical moiety that upon degradation of the polymer, forms a pharmaceutically active agent. [82] Another embodiment provides a composition comprising a biodegradable polymer linked to a chemical moiety through at least one covalent bond, wherein the chemical moiety forms a pharmaceutically active agent upon degradation of the covalent bond, and wherein the polymer has a Tg greater than 50°C. Another embodiment provides the composition applied to at least a portion of a surface of a medical device, such as an implantable medical device.
[83] Another embodiment provides a composition applied to the surface of a medical device, such as an implantable medical device, comprising a prodrug of an antiproliferative active agent , wherein the prodrug comprises: an active antiproliferative agent [D] covalently bonded to, a hydrolysable linker group [H] covalently bonded to, a chemical moiety [C] of sufficient size and hydrophobicity to reduce the aqueous solubility of the composition to below that of the antiproliferative agent in free form.
[84] In one embodiment, [C] is a polymer with a molecular weight greater than 1 ,000 Da.
[85] In one embodiment, [C] is a polymer with a molecular weight greater than 10,000 Da.
[86] In one embodiment, [C] is a polymer comprising at least one monomeric unit selected from lactic acid, glycolic acid, caprolactone, lactide, glycolide, and thmethyl carbonate.
[87] In one embodiment, [C] is a polymer comprising long chain aliphatic hydrocarbons.
[88] In one embodiment, [C] is a polymer comprising aliphatic hydrocarbon chains of at least 6 carbon atoms.
[89] In one embodiment, [C] is a polymer comprising aliphatic hydrocarbon chains of at least 12 carbon atoms.
[90] Another embodiment provides a composition comprising a biodegradable polymer, the biodegradable polymer being linked to a chemical moiety through a covalent bond, wherein, the chemical moiety forms a pharmaceutically active agent upon degradation of the covalent bond, the composition (e.g., the polymer) is less soluble in an aqueous medium than the free form of the pharmaceutically active agent, and the polymer has a Tg greater than 50°C.
BRIEF DESCRIPTION OF THE DRAWINGS
[91] Various embodiments of the invention will be understood from the following description, the appended claims and the accompanying drawings, in which:
[92] FIG. 1 is a schematic showing a paclitaxel polymer via a covalent linking group; and
[93] FIG. 2 is a schematic of a multi-layered coating containing different pharmaceutically active agents.
DETAILED DESCRIPTION
[94] One embodiment provides a prodrug for at least one coating covering all or a portion of an implantable medical device. In one embodiment, a composition is provided comprising a biodegradable polymer, the biodegradable polymer being linked to a chemical moiety through a covalent bond, wherein, the chemical moiety forms a pharmaceutically active agent upon degradation of the covalent bond.
[95] Upon degradation of the covalent bond, the chemical moiety forms a pharmaceutically active agent in its free form. The "free form" of the pharmaceutically active agent can refer to the neutral compound, or salts thereof, e.g., the isolable or stable form of the agent. Thus, the present invention relates to those compositions (comprising the chemical moiety) having a lower solubility in aqueous media (or in physiological media), than the free form of the pharmaceutically active agent. Often during treatment of a disease or condition with a medical device having a coating comprising a drug, the drug is washed away when or after being inserted into a mammal prior to its reaching the target site. In one embodiment, a coating comprising a drug in a form affording it reduced solubility can provide a lesser probability of the drug being inadvertently eliminated by dissolution (or partial dissolution) prior to its reaching the target site.
[96] In one embodiment, the composition (e.g., the polymer) is less soluble in an aqueous medium than the free form of the pharmaceutically active agent. However, depending on the structure of the polymer, the composition (e.g., the polymer) can be tailored to be more soluble in an aqueous medium than the free form of the pharmaceutically active agent.
[97] In another embodiment, the polymer has a Tg greater than 37°C, such as a Tg greater than 40°C or a Tg greater than 50°C.
[98] In one embodiment, a product of the degradation or hydrolysis is the pharmaceutically active agent, e.g., the free form of the agent. In another embodiment, the pharmaceutically active agent has a different structure than the free form of the pharmaceutically active agent but is the true active species that treats the disease or condition, e.g., the form of the agent in vivo.
[99] In one embodiment, the biodegradable polymer is linked to the chemical moiety. In one embodiment, the biodegradable polymer is linked to a pendant chemical moiety. In another embodiment, a "biodegradable polymer linked to a chemical moiety" refers to a chemical moiety incorporated in the backbone of the biodegradable polymer. In one embodiment, it is the biodegradable polymer that reduces the solubility of the agent.
[100] In one embodiment, the degradation of the covalent bond occurs via hydrolysis. The hydrolysis can involve a direct reaction with an aqueous medium, or can be catalyzed chemically or enzymatically. "Aqueous medium" refers to water, aqueous solutions, physiological media or biological fluids (e.g., body fluids), and other pharmaceutically acceptable media. Suitable hydrolysable covalent bonds include those forming esters, amides, urethanes, carbamates, carbonates, azo linkages, anhydrides, thioesters, and combinations thereof.
[101] In one embodiment, an ester linkage has the formula -OC(=O)-. In one embodiment, a thioester linkage has the formula -SC(=O)-. In one embodiment, an amide linkage has the formula -N(R)C(=O)-, wherein R is a suitable organic radical, such as, for example, hydrogen, (C1 -C6)alkyl, (C3 -C6)cycloalkyl, (C3 - C6)cycloalkyl(C1 -C6)alkyl, aryl, heteroaryl, aryl(C1 -C6)alkyl, or heteroaryl(C1 - C6)alkyl. In one embodiment, a carbamate linkage has the formula -OC(=O)N(R)-, wherein each R is a suitable organic radical as described above. In one embodiment, a "carbonate" linkage has the formula -OC(=O)O-. In one embodiment, an anhydride linkage has the formula -C(=O)-O-C(=O)-. In one embodiment, an azo linkage has the formula -N=N-.
[102] In one embodiment, the polymer (i.e., the polymer containing the covalently linked chemical moiety) is biodegradable. "Biodegradable polymer," as used herein, refers to a polymer capable of hydrolyzing or otherwise degrading in an aqueous medium, as opposed to being soluble in an aqueous medium without degradation. In one embodiment, the resulting product(s) of biodegradation is soluble in the resulting body fluid or, if insoluble, can be suspended in a body fluid and transported away from the implantation site without clogging the flow of the body fluid. The body fluid can be any fluid in the body of a mammal including, but not limited to, blood, serum, urine, saliva, lymph, plasma, gastric, biliary, or intestinal fluids, seminal fluids, and mucosal fluids, humors, and extracellular fluids. In one embodiment, the biodegradable polymer is soluble, degradable as defined above, or is an aggregate of soluble and/or degradable matehal(s) with insoluble matehal(s) such that, with the resorption of the soluble and/or degradable materials, the residual insoluble materials are of sufficiently fine size such that they can be suspended in a body fluid and transported away from the implantation site without clogging the flow of the body fluid. Ultimately, the degraded compounds can be eliminated from the body either by excretion in perspiration, urine or feces, or dissolved, degraded, corroded or otherwise metabolized into soluble components that are then excreted from the body.
[103] In one embodiment, the biodegradable polymer imparts at least one mechanical property to the composition, such as adhesion, mechanical integrity, and coating properties. In one embodiment, the biodegradable polymer imparts at least one chemical property, such as chemical stability or reduced solubility in an aqueous medium.
[104] In one embodiment, any of the polymers disclosed herein has a Tg of greater than 37°C. In another embodiment, the Tg is greater than 40°C, greater than 50°C, or even greater than 60°C. [105] In one embodiment, the biodegradable polymers are degraded through cleavage of functional groups such as esters, anhydrides, carbonates, thioesters, orthoesters, glycosidic bonds, phosphate esters, and amides. Suitable biodegradable polymers include those in the FDA GRAS (Generally Regarded As Safe) list, the disclosure of which is incorporated herein by reference. Exemplary biodegradable polymers include polyglycolides, polylactides (e.g., poly-l- lactide (PLLA)), polycaprolactones, polydioxanones, poly(lactide-co-glycolide) (PLGA), polyhydroxybutyrate, polyhydroxyvalerate, polyphosphoesters, polyphosphoester-urethane, polyamino acids, polycyanoacrylates, poly(thmethylene carbonate), biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen, and blends and copolymers thereof.
[106] In one embodiment, the biodegradable polymer is present in the composition in an amount ranging from 25% to 99% by weight relative to the total weight of the composition, such as an amount ranging from 25% to 95%, from 40% to 99%, or ranging from 40% to 95%.
[107] In one embodiment, the biodegradable polymer comprises PLA in an amount ranging from 15% to 100% by weight relative to the total weight of the biodegradable polymer.
[108] In one embodiment, the biodegradable polymer comprises a blend of polymers. An exemplary blend is PLGA and D1L-PLA. In one embodiment, the biodegradable polymer comprises a blend of 15-85% PLGA, by weight relative to the total weight of the biodegradable polymer, with the remainder PLA.
[109] In one embodiment, the "chemical moiety" is a fragment of a pharmaceutically active agent. For example, upon reacting the pharmaceutically active agent with another species (e.g., a polymer or linker), the portion of the agent that is covalently bonded is the chemical moiety of the agent. A biodegradable polymer "linked to a chemical moiety through a covalent bond" can refer to one or more covalent bonds. Accordingly, in one embodiment, the chemical moiety is linked directly to the polymer via one or more covalent bonds. "Linked directly" as used herein refers to the product of a reaction between the polymer and the pharmaceutically active agent, where the linking atom originates from the starting materials. In another embodiment, the chemical moiety is linked to the biodegradable polymer through covalent bond(s) to a linking group (comprising one or more molecules) or spacer that is covalently bonded to the polymer. Here, the linking group comes from an external reagent and does not originate from either the polymer or the pharmaceutically active agent. Suitable linking groups bind the biodegradable polymer to the chemical moiety through covalent bonds, such as those covalent linkages described herein, e.g., ester, amide, carbamate, carbonate, azo, anhydride, and thioester linkages. Other methods for covalently incorporating pharmaceuticals are provided in Qiu et al., "Polymer Architecture and Drug Delivery," Pharmaceutical Research, Vol. 23, No. 1 , pp. 1 -30 (2006), the disclosure of which is incorporated herein by reference.
[110] FIG. 1 shows a schematic of a chemical moiety covalently linked to a biodegradable polymer. The chemical moiety of FIG. 1 is paclitaxel (PAC), shown below:
Figure imgf000017_0001
paclitaxel (PAC)
[111] In FIG. 1 , a linking group containing two carbonyl chloride functional groups (acyl chlorides if L is, e.g., an alkyl group), is reacted with a hydroxyl group of paclitaxel in the presence of triethylamine (TEA). The resulting -[C(=O)-L-C(=O)-O-PAC-O]- unit can be covalently bonded to a second such unit, and/or can be covalently bonded to another species, such as a polymer (e.g., a biodegradable polymer) via its residual carbonyl chloride group or via a subsequently introduced second linker group. In another embodiment, the L is a biodegradable polymer, resulting in the paclitaxel being directly bonded to the polymer. In either embodiment, the paclitaxel is bonded to the polymer via a series of carbonate/ester linkages, and other linkages such as anhydride, carbamate, etc., depending on the linking group and polymers.
[112] Another embodiment provides a composition for coating at least a portion of a medical device, comprising at least two repeat units, each repeat unit comprising a chemical moiety covalently bonded to least one hydrolysable linking group wherein, the chemical moiety forms a pharmaceutically active agent upon hydrolysis of the covalent bond.
[113] In one embodiment, the composition (e.g., the polymer) has reduced solubility in an aqueous medium than the free form of the pharmaceutically active agent. In another embodiment, the composition (e.g., the polymer) has increased solubility in an aqueous medium than the free form of the pharmaceutically active agent.
[114] In one embodiment, the polymer has a Tg greater than 37°C, such as a Tg greater than 40°C, a Tg greater than 50°C, or a Tg greater than 60°C.
[115] In one embodiment, a "repeat unit comprising" refers to a composition that can have additional linking groups and species other than the repeat unit listed herein.
[116] In one embodiment, more than one pharmaceutically active agent other than the agent covalently bonded can be incorporated in the polymer. The additional agents can be either covalently bonded to the polymer or even admixed with the polymer, so long as at least one agent is covalently bonded to the polymer.
[117] In one embodiment, the linking group can impart mechanical properties and release kinetics for the selected therapeutic application. In one embodiment, the linking group is a divalent organic radical having a molecular weight ranging from 25 daltons to 400 daltons, e.g., a molecular weight ranging from 40 daltons to 200 daltons.
[118] In one embodiment, the linking group has a length ranging from 5 angstroms to 100 angstroms using standard bond lengths and angles, e.g., a length ranging from 10 angstroms to 50 angstroms. [119] The linking group may be biologically inactive, or may itself possess biological activity. The linking group can also comprise other functional groups (including hydroxy groups, mercapto groups, amine groups, carboxylic acids, as well as others) that can be used to modify the properties of the polymer (e.g. for branching, for cross linking, for appending other molecules (e.g. another biologically active compound) to the polymer, for reducing the solubility of the polymer, or for effecting the biodisthbution of the polymer).
[120] In one embodiment, the linking group is: a (C1 -C6)alkyl, e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, 3-pentyl, or hexyl; (C3 - C6)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (C3 - C6)cycloalkyl(C1 -C6)alkyl can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2- cyclopentylethyl, or 2-cyclohexylethyl; (C1 -C6)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; (C1 -C6)alkanoyl can be acetyl, propanoyl or butanoyl; (C1 - C6)alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, or hexyloxycarbonyl; (C1 - C6)alkylthio can be methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, or hexylthio; (C2 -C6)alkanoyloxy can be acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, or hexanoyloxy; aryl can be phenyl, indenyl, or naphthyl; and heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyhmidinyl (or its N-oxide), indolyl, isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide).
[121] In one embodiment, the linking group is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 20 carbon atoms, wherein the chain is optionally substituted on carbon with one or more (e.g. 1 , 2, 3, or 4) substituents selected from (C1 -C6)alkoxy, (C3 -C6)cycloalkyl, (C1 - C6)alkanoyl, (C1 -C6)alkanoyloxy, (C1 -C6)alkoxycarbonyl, (C1 -C6)alkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy.
[122] In another embodiment, the linking group is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 20 carbon atoms, wherein one or more (e.g. 1 , 2, 3, or 4) of the carbon atoms is optionally replaced by (-O-) or (-NR-).
[123] In another embodiment, the linking group is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 3 to 15 carbon atoms, wherein one or more (e.g. 1 , 2, 3, or 4) of the carbon atoms is optionally replaced by (-O-) or NR-), and wherein the chain is optionally substituted on carbon with one or more (e.g. 1 , 2, 3, or 4) substituents selected from (Cr C6)alkoxy, (C3-C6)cycloalkyl, (C1 -C6)alkanoyl, (C1 -C6)alkanoyloxy, (C1- C6)alkoxycarbonyl, (C1 -C6)alkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy.
[124] In another embodiment, the linking group is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 3 to 15 carbon atoms, wherein one or more (e.g. 1 , 2, 3, or 4) of the carbon atoms is optionally replaced by (-O-) or (-NR-).
[125] Other linking groups are disclosed in U.S. Patent Nos. 6,613,807, and 6,685,928, and U.S. Patent Publication Nos. 20060188546 and 20050031577, the disclosures of which are incorporated herein by reference.
[126] In another embodiment, the linking group is selected from amino acids and peptides.
[127] In one embodiment, the linking group is present in an amount ranging from 5% to 50% by weight relative to the total weight of the composition.
[128] Exemplary pharmaceutically active agents include antiproliferative agents (e.g., those active against smooth muscle cells), anti-inflammatory agents, and healing promoters. Exemplary antiproliferative agents include paclitaxel, sirolimus, everolimus, biolimus, zotarolimus, AP23573 (a sirolimus analog), and other limus derivatives. Exemplary anti-inflammatory agents include non-steroidal agents (e.g., 3-amino-4-hydroxybutyric acid, aceclofenac, alminoprofen, bromfenac, bumadizon, carprofen, diclofenac, diflunisal, enfenamic acid, etodolac, fendosal, flufenamic acid, gentisic acid, meclofenamic acid, mefenamic acid, mesalamine, niflumic acid, olsalazine oxaceprol, S-adenosylmethionine, salicylic acid, salsalate, sulfasalazine, tolfenamic acid). Exemplary healing promoters include nitric oxide donors such as halofuganone, S-nitrosothiols, and glyceryl thnitrite 1 -[N-(3- aminopropyl)-N-(3-ammoniopropyl]diazen-1 -ium-1 ,2-diolate, 1 -[N-(2-aminoethyl)-N- (2-annnnonioethyl)annino]diazen-1 -iunn-1 ,2-diolate, as well as epidermal growth factor and other growth factors.
[129] Other exemplary pharmaceutically active agents include analgesics, anesthetics, anti acne agents, antibiotics, synthetic antibacterial agents, anticholinergics, anticoagulants, antidyskinetics, antifibrotics, antifungal agents, antiglaucoma agents, anti-inflammatory agents, antineoplastics, antiosteoporotics, antipagetics, anti-Parkinson's agents, antisporatics, antipyretics, antiseptics/disinfectants, antithrombotics, bone resorption inhibitors, calcium regulators, keratolytics, sclerosing agents and ultraviolet screening agents. Exemplary antithrombotics and anticoagulants include aspirin and plavix.
[130] In one embodiment, the pharmaceutically active agent is a drug useful for treating diseases and conditions associated with restenosis, e.g., antithrombotics, anticoagulants, antiplatelet agents, thrombolytics, antiproliferatives, antiinflammatories, antimitotic, antimicrobial, agents that inhibit restenosis, smooth muscle cell inhibitors, antibiotics, fibrinolytic, immunosuppressive, and anti-antigenic agents.
[131] Examples of anti-bacterial compounds suitable for use in the present invention include, but are not limited to, 4-sulfanilamidosalicylic acid, acediasulfone, amfenac, amoxicillin, ampicillin, apalcillin, apicycline, aspoxicillin, aztreonam, bambermycin(s), biapenem, carbenicillin, carumonam, cefadroxil, cefamandole, cefatrizine, cefbuperazone, cefclidin, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefinenoxime, cefminox, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotetan, cefotiam, cefozopran, cefpimizole, cefpiramide, cefpirome, cefprozil, cefroxadine, ceftazidime, cefteram, ceftibuten, ceftriaxone, cefuzonam, cephalexin, cephaloglycin, cephalosporin C, cephradine, ciprofloxacin, clinafloxacin, cyclacillin, enoxacin, epicillin, flomoxef, grepafloxacin, hetacillin, imipenem, lomefloxacin, lymecycline, meropenem, moxalactam, mupirocin, nadifloxacin, norfloxacin, panipenem, pazufloxacin, penicillin N, pipemidic acid, quinacillin, ritipenem, salazosulfadimidine, sparfloxacin, succisulfone, sulfachrysoidine, sulfaloxic acid, teicoplanin, temafloxacin, temocillin, ticarcillin, tigemonam, tosufloxacin, trovafloxacin, and vancomycin. [132] Examples of anti-fungal compounds suitable for use in the present invention include, but are not limited to amphotericin B, azasehne, candicidin(s), lucensomycin, natamycin, and nystatin.
[133] Examples of anti-neoplastic compounds suitable for use in the present invention include, but are not limited to 6-diazo-5-oxo-L-norleucine, azaserine, carzinophillin A, denoptehn, edatrexate, eflomithine, melphalan, methotrexate, mycophenolic acid, podophyllinic acid 2-ethylhydrazide, pteroptehn, streptonigrin, Tomudex.RTM. (N-((5-(((1 ,4-Dihydro-2-methyl-4-oxo-6- quinazolinyl)methyl)methylamino)-2- thienyl)carbonyl)-L-glutamic acid), and ubenimex.
[134] Examples of anti-thrombotic compounds for use in the present invention include, but are not limited to, argatroban, iloprost, lamifiban, taprostene, and tirofiban.
[135] Examples of immunosuppressive compounds suitable for use in the present invention include, but are not limited to bucillamine, mycophenolic acid, procodazole, romurtide, and ubenimex.
[136] Dosages of the pharmaceutically active agent may be determined by means known in the art. Typically, the dosage is dependent upon the particular drug employed and medical condition being treated to achieve a therapeutic result. In one embodiment, the amount of drug represents about 0.001 percent to about seventy percent of the total coating weight, or about 0.01 percent to about sixty percent of the total coating weight. In one embodiment, the weight percent of the therapeutic agents in the carrier or polymer coating is 1 % to 50%, 2% to 45%, 5% to 40%, or 10% to 25% by weight relative to the total coating weight. In another embodiment, it is possible that the drug may represent as little as 0.0001 percent to the total coating weight. In another embodiment, the dosage is determined per coated surface area of the device. For example, the dose density may range from 0.05 to 10 μg/mm2, such as a dose-density ranging from 0.05 to 1.0 μg/mm2, or ranging from 0.1 to 4 μg/mm2, or ranging from 0.2 to 4 μg/mm2.
[137] In one embodiment, the device delivers the agent over a selected period of time, such as days, weeks or months, e.g., such as a period of at least one week, at least two weeks, at least one month, at least six months, or at least one year.
[138] In one embodiment, the number average molecular weight of the polymer is 20,000 Da or less, such as a number average molecular weight of 10,000 Da or less, or 5,000 Da or less. In one embodiment, the number average molecular weight of the polymer ranges from 5,000 daltons to 100,000 daltons. In another embodiment, the number average molecular weight of the polymer is 25,000 Da or less. In yet another embodiment, the number average molecular weight of the polymer ranges from 25,000 daltons to 100,000 daltons.
[139] Another embodiment provides a polymeric material comprising: a first biodegradable polymer portion comprising a chemical moiety of a pharmaceutically active agent bonded to a spacer group to form a backbone of the first polymer portion; a second biodegradable polymer portion bonded to the first polymer portion; wherein the pharmaceutically active agent is bonded to the spacer group via a linkage that is naturally hydrolysable in an in vivo environment, the polymeric material being less soluble in vivo than the free form of the pharmaceutically active agent is soluble in vivo.
[140] In one embodiment, the at least one pharmaceutically active agent is hydrophobic or amphipathic (e.g., paclitaxel). Although hydrophobic agents may have some solubility in water, generally a hydrophobic agent generally dissolves more readily in oils or non-polar solvents than in water or polar solvents. In one embodiment, the agent is hydrophilic, e.g., dissolves more readily in water or polar solvents than in oils or non-polar solvents.
[141] In another embodiment, the composition comprises a polymer comprising the repeat unit:
-[D1-L1-D2-L2-D3-L3-BP]- wherein:
L1, L2, and L3 can be the same or different and are linking groups, D1 is a chemical moiety that upon degradation of covalent bonds binding it to a linking group and BP, forms an antiproliferative pharmaceutically active agent,
D2 is a chemical moiety that upon degradation of covalent bonds binding it to linking groups, forms an anti-inflammatory agent,
D3 is a chemical moiety that upon degradation of covalent bonds binding it to linking groups, forms a healing promoter, and
BP is a biodegradable polymer, such as the polymers disclosed herein.
[142] In one embodiment, the polymer is less soluble in an aqueous medium (e.g., a physiological medium) than is the free form of any of the pharmaceutically active agents Di, D2, and D3.
[143] In this embodiment, various drugs are incorporated in the polymer to impart different therapeutic effects. The choice of L1, L2, L3, and the biodegradable polymer can allow control of release profile and kinetics of pharmaceutically active agents from the medical device. For example, the release profile and kinetics can be controlled by the hydrolysis rates and chemistry of the various hydrolytic linkages. The period of time of drug delivery and drug dosage can be controlled to substantially prevent undesirable burst release. Moreover, the linking groups and biodegradable polymer can be chosen to provide desirable mechanical properties.
[144] In one embodiment, a "polymer comprising the repeat unit" can have additional linking groups and repeat units other than the repeat unit listed herein.
[145] In another embodiment, pharmaceutically active agents in addition to D1, D2, and D3 can also be present in the composition, e.g., any other agents useful for treating vascular injury, e.g., restenosis. Alternatively, pharmaceutically active agents in addition to D1 , D2, and D3 can be incorporated in the polymer, e.g., either covalently linked to the polymer or admixed with the polymer.
[146] In one embodiment, the composition comprises a polymer comprising the repeat unit:
-[D-BP]- wherein:
BP is derived from a biodegradable polymer; and D is a chemical moiety that releases a pharmaceutically active agent upon degradation of the covalent bond to BP, e.g., upon hydrolysis of covalent bonds binding it to BP.
[147] In one embodiment, D is a chemical moiety that releases rapamycin and/or paclitaxel. In one embodiment, BP is derived from one or more polymers selected from PLLA, PDLA, PDLLA, PGA, PLGA, polycaprolactone, polydioxinone, polymers prepared from mono and/or bis-carboxymethyl-polyethyleneglycol, and poly amino acids prepared from one or more monomers such as glycine, alanine, leucine, isoleucine, norleucine, valine, norvaline, methionine, phenylalanine, and tryptophan.
[148] In one embodiment, the composition comprises a polymer comprising the repeat unit:
-[(D-L)n-BP]- wherein:
L is a linker derived from one or more molecules selected from diacids, diols, diamines, hydroxyacids, amino acids, and other difunctional molecules that can be bonded to D and to BP;
D is a chemical moiety that releases a pharmaceutically active agent upon degradation of the covalent bond, e.g., upon hydrolysis of covalent bonds binding it to L and BP;
BP is derived from a biodegradable polymer that can be bonded to L and D; and n is either 1 , 2, 1 -5, 1 -20, 1 -50, 1 -100 or 1 -500.
[149] In one embodiment L is derived from one or more molecules selected from carbonic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, pimelic acid, adipic acid, and sebacic acid. In one embodiment, BP is derived from one or more polymers selected from PLLA, PDLA, PDLLA, PGA, PLGA, polycaprolactone, polydioxinone, polymers prepared from mono and/or bis-carboxymethyl- polyethyleneglycol, and poly amino acids prepared from one or more monomers selected from glycine, alanine, leucine, isoleucine, norleucine, valine, norvaline, methionine, phenylalanine, and tryptophan. In one embodiment, D is a chemical moiety that releases rapamycin and/or paclitaxel. [150] In one embodiment, the composition comprises a polymer comprising the repeat unit:
Figure imgf000026_0001
wherein:
L is a linker derived from one or molecules selected from triacids, dihydroxy acids, hydroxy diacids, amino diacids, diamino acids, and other trifunctional molecules that can be bonded to D and to BP;
D is a chemical moiety that releases a pharmaceutically active agent upon degradation of the covalent bond, e.g., upon hydrolysis of covalent bonds binding it to L;
BP is derived from a biodegradable polymer that can be bonded to L; and n is either 1 , 2, 1 -5, 1 -20, 1 -50, 1 -100 or 1 -500.
[151] In one embodiment L is derived from one or more of glutamic acid, aspartic acid and/or glyceric acid, D is a chemical moiety that releases rapamycin or paclitaxel, and BP is derived from one or more of PLLA, PDLA, PDLLA, PGA, PLGA, polycaprolactone, polydioxinone, mono-carboxyethyl-polyethyleneglycol, and/or poly amino acids prepared from one or more monomers selected from glycine, alanine, leucine, isoleucine, norleucine, valine, norvaline, methionine, phenylalanine, and tryptophan.
[152] In one embodiment, the composition comprises a polymer comprising the repeat unit:
Figure imgf000026_0002
wherein:
L is a linker derived from one or more molecules selected from triacids, dihydroxy acids, hydroxy diacids, amino diacids, diamino acids, and other trifunctional molecules that can be bonded to D and to BP; D is a chemical moiety that releases a pharmaceutically active agent upon hydrolysis of covalent bonds binding it to L and BP;
BP is derived from a biodegradable polymer that can be bonded to L and D; and n is either 1 , 2, 1 -5, 1 -20, 1 -50, 1 -100, or 1 -500.
[153] In one embodiment L is derived from 2-carboxyglutaric acid, D is a chemical moiety that releases rapamycin or paclitaxel, and BP is derived from one or more of PLLA, PDLA, PDLLA, PGA, PLGA, polycaprolactone, polydioxinone, polymers prepared from mono and/or bis-carboxyethyl-polyethyleneglycol, and poly amino acids prepared from one or more monomers selected from glycine, alanine, leucine, isoleucine, norleucine, valine, norvaline, methionine, phenylalanine, and tryptophan.
[154] In another embodiment L is derived from one or more of glutamic acid, aspartic acid or glyceric acid, D is a chemical moiety that releases rapamycin and/or paclitaxel, and BP is derived from bis-carboxymethyl-polyethyleneglycol.
[155] In one embodiment, two or more coatings are applied to the device where each coating contains a different pharmaceutically active agent. FIG. 2 is a schematic showing a multi-layered coating arrangement, where each of layers 1 , 2, and 3 contain either a unique pharmaceutically active agent, or if two or more layers contain the same agent, the agent is linked to the polymer via a different linking chemistry. This arrangement allows control of the release profile of the agents and can provide control of the sequence of release of different pharmaceutically active agents. In one embodiment, each layer can be individually customized by choice of agents, linking chemistry, polymer structure, thickness, etc. for controlling the release profile and kinetics.
[156] In one embodiment, each layer contains a unique agent, e.g., Di, D2, and D3, as described herein, or any other agents useful for treating vascular injury, e.g., restenosis. Alternatively, pharmaceutically active agents in addition to Di, D2, and D3 can be incorporated in the polymer, e.g., either covalently linked to the polymer or admixed with the polymer.
[157] In one embodiment, the device treats narrowing or obstruction of a body passageway in a subject in need thereof. In another embodiment, the method comprises inserting the device into the passageway, the device comprising a generally tubular structure, the surface of the structure being coated with a composition disclosed herein, such that the passageway is expanded. In the method, the body passageway may be selected from arteries, veins, lacrimal ducts, trachea, bronchi, bronchiole, nasal passages, sinuses, eustachian tubes, the external auditory canal, oral cavities, the esophagus, the stomach, the duodenum, the small intestine, the large intestine, biliary tracts, the ureter, the bladder, the urethra, the fallopian tubes, uterus, vagina, the vasdeferens, and the ventricular system.
[158] In one embodiment, the implantable devices disclosed herein are implanted in a subject in need thereof to achieve a therapeutic effect, e.g., therapeutic treatment and/or prophylactic/preventative measures. Those in need of treatment may include individuals already having a particular medical disease as well as those at risk for the disease (e.g., those who are likely to ultimately acquire the disorder). A therapeutic method can also result in the prevention or amelioration of symptoms, or an otherwise desired biological outcome, and may be evaluated by improved clinical signs, delayed onset of disease, reduced/elevated levels of lymphocytes and/or antibodies.
[159] In one embodiment, the method is used for treating at least one disease or condition associated with vascular injury or angioplasty, e.g., one or more of atherosclerosis, restenosis, neointima, neointimal hyperplasia and thrombosis.
[160] Exemplary devices include sutures, staples, anastomosis devices, vertebral disks, bone pins, suture anchors, hemostatic barriers, clamps, screws, plates, clips, vascular implants, urological implants, tissue adhesives and sealants, tissue scaffolds, bone substitutes, intraluminal devices, and vascular supports. For example, the device can be a cardiovascular device, such as venous catheters, venous ports, tunneled venous catheters, chronic infusion lines or ports, including hepatic artery infusion catheters, pacemakers and pace maker leads, and implantable defibrillators. Alternatively, the device can be a neurologic/neurosurgical device such as ventricular peritoneal shunts, ventricular atrial shunts, nerve stimulator devices, dural patches and implants to prevent epidural fibrosis post- laminectomy, and devices for continuous subarachnoid infusions. The device can be a gastrointestinal device, such as chronic indwelling catheters, feeding tubes, portosystemic shunts, shunts for ascites, peritoneal implants for drug delivery, peritoneal dialysis catheters, and suspensions or solid implants to prevent surgical adhesions. In another example, the device can be a genitourinary device, such as uterine implants, including intrauterine devices (IUDs) and devices to prevent endometrial hyperplasia, fallopian tubal implants, including reversible sterilization devices, fallopian tubal stents, artificial sphincters and periurethral implants for incontinence, ureteric stents, chronic indwelling catheters, bladder augmentations, or wraps or splints for vasovasostomy, central venous catheters.
[161] Other exemplary devices include prosthetic heart valves, vascular grafts ophthalmologic implants (e.g., multino implants and other implants for neovascular glaucoma, drug eluting contact lenses for pterygiums, splints for failed dacrocystalrhinostomy, drug eluting contact lenses for corneal neovascularity, implants for diabetic retinopathy, drug eluting contact lenses for high risk corneal transplants), otolaryngology devices (e.g., ossicular implants, Eustachian tube splints or stents for glue ear or chronic otitis as an alternative to transtempanic drains), plastic surgery implants (e.g., breast implants or chin implants), and catheter cuffs and orthopedic implants (e.g., cemented orthopedic prostheses).
[162] In one embodiment, the device is selected from pacemaker leads, valve replacement and repair devices, vena cava filters, and embolic coils and beads.
[163] Another exemplary device according to the invention is a stent, such as a stent comprising a generally tubular structure. A stent is commonly used as a tubular structure disposed inside the lumen of a duct to relieve an obstruction. In one embodiment, the stent is either balloon expandable or self-expanding. Commonly, stents are inserted into the lumen in a non-expanded form and are then expanded autonomously, or with the aid of a second device in situ. A typical method of expansion occurs through the use of a catheter-mounted angioplasty balloon which is inflated within the stenosed vessel or body passageway in order to shear and disrupt the obstructions associated with the wall components of the vessel and to obtain an enlarged lumen. [164] An exemplary stent is a stent for treating narrowing or obstruction of a body passageway in a human or animal in need thereof. "Body passageway" as used herein refers to any of number of passageways, tubes, pipes, tracts, canals, sinuses or conduits which have an inner lumen and allow the flow of materials within the body. Representative examples of body passageways include arteries and veins, lacrimal ducts, the trachea, bronchi, bronchiole, nasal passages (including the sinuses) and other airways, eustachian tubes, the external auditory canal, oral cavities, the esophagus, the stomach, the duodenum, the small intestine, the large intestine, biliary tracts, the ureter, the bladder, the urethra, the fallopian tubes, uterus, vagina and other passageways of the female reproductive tract, the vasdeferens and other passageways of the male reproductive tract, and the ventricular system (cerebrospinal fluid) of the brain and the spinal cord. Exemplary devices of the invention are for these above-mentioned body passageways, such as stents, e.g., vascular stents. There is a multiplicity of different vascular stents known in the art that may be utilized following percutaneous transluminal coronary angioplasty.
[165] Any number of stents may be utilized in accordance with the present invention and the invention is not limited to the specific stents that are described in exemplary embodiments of the present invention. The skilled artisan will recognize that any number of stents may be utilized in connection with the present invention. In addition, as stated above, other medical devices may be utilized, such as e.g., orthopedic implants.
[166] In one embodiment, the composition is coated on the stent to form a conformal coating around all surfaces of the stent. In another embodiment, the composition is coated only on the abluminal surface of the stent. In one embodiment, the composition resides partially or completely within micro-reservoirs or pores in the stent surface.
[167] In one embodiment, the device is an angioplasty balloon having coated thereon the coating comprising the composition, wherein the balloon is used to deliver the composition to an endoluminal surface.
[168] The devices of the invention may be coated partially or wholly with the above defined compositions in any manner known in the art, e.g., dipping, spraying, rolling, brushing, electrostatic plating or spinning, vapor deposition (e.g., physical or chemical), air spraying including atomized spray coating, and spray coating using an ultrasonic nozzle. The compositions can be applied by these methods either as a solid (e.g., film or particles), a suspension, a solution, or as a vapor. Alternatively, the device can be coated with a first substance (such as a hydrogel) that is capable of absorbing the composition. In another embodiment, the device can be constructed from a material comprising a polymer/drug composition.
EXAMPLES
[169] For purposes of illustration, immediately following are described certain examples of synthetic schemes and polymers according to the invention.
Example 1
1. Materials
[01] Ampicillin, paclitaxel and rapamycine were obtained from Huei-Ho international Co LTDchina. Dimethylformamide (DMF), pyridine, triethylamine, acetic anhydride, methylene chloride (anhydrous), and diethyl ether were purchased from Finar & SDfine chemical. All other fine chemicals and solvents were obtained from SDfine chemical HYD. Triethylamine was dried over calcium hydride (CaC^) and all other reagents were used with no further purification.
2. Analysis Methods
2.1. Proton Nuclear Magnetic Resonance (1 H NMR) Spectroscopy
[02] Proton nuclear magnetic resonance (1 H NMR) spectra were recorded on a Varian 300 MHz spectrometer. The samples (5-10 mg) were dissolved in a deuterated solvent (DMSO-c/6), which was also used as the internal reference.
2.2. Gel Permeation Chromatography (GPC)
[03] Weight-averaged molecular weights (Mw) and polydispersity indexes (PDI) were determined by gel permeation chromatography (GPC). Synthesis Scheme: 1
Figure imgf000032_0001
3.0. Ampicillin with sebacoyl chloride
[04] Ampicillin (1.4g, 4.8mnnol) was added to DMF (25ml_) and pyridine (1.69ml_, 20mnnol) to a suspension. Sebacoyl chloride (0.5ml_, 2.09mmol) dissolved in dimethylformamide (5ml_) was added drop wise over 5 minutes to the stirring reaction mixture at 0 °C to afford a clear solution. The reaction was stirred for 2h at 0°C, poured over water (10OmL) and acidified to pH~2 using 0.1 N hydrochloric acid solution while stirring. The white solid (Ampicillin-sebacic diacid, 1 ) that formed was isolated by vacuum filtration, washed with water (2x50ml_) and dried overnight under vacuum at room temperature. Ampicillin-sebacic Diacid (1). Yield: 70% (white powder). 1 H NMR (DMSOd6): δ 9.10 (d, 2H, NH), 8.50 (d, 2H, NH), 7.45-7.20 (m, 10H, ArH), 5.75 (d, 2H, CH), 5.55-5.50 (m, 2H, CH), 5.40 (d, 2H, CH), 4.20 (s, 2H, CH), 2.25-2.20 (m, 4H, CH2), 1.65-1.35 (m, 12H, CH2), 1.20 (s, 12H, CH3). Mass= [M+H] 865. 3.1 Ampicillin-sebacic diacid -Poly(anhydride-amide)
[05] Ampicillin-sebacic diacid (1) (1.2g, 1.38mnnol) was dissolved in CH2CI2 (2OmL) and thethylamine (0.8mL, 6.52mmol). Triphosgene (0.045g, 1.52mmol) dissolved in dichloromethane (5ml_) was added drop wise over 15 minutes to the stirring reaction mixture at 0 °C to afford a suspension. The reaction was stirred for 2 h at 0 °C under nitrogen and poured over diethyl ether (5OmL). The solid (polymer, 2) that formed was isolated by vacuum filtration, washed with acidic water (2x50mL) and dried overnight under vacuum at room temperature. Poly-ampicillin-sebacic (2). Yield: quantitative (light yellow powder). 1 H NMR (DMSO-c/6): δ 9.10 (d, 2H, NH), 8.45 (d, 2H, NH), 7.45-7.20 (m, 10H, ArH), 5.75 (d, 2H, CH), 5.55-5.50 (m, 2H, CH), 5.35 (d, 2H, CH), 4.20 (s, 2H, CH), 2.25-2.20 (m, 4H, CH2), 1.60-1.30 (m, 12H, CH2), 1.15 (s, 12H, CH3). Melting point = 184 °C.
Example 2
Synthesis Scheme: 2
Figure imgf000033_0001
3.2. Ampicillin with adipoyl chloride
[06] Ampicillin (1.9g, 5.46mnnol) was added to DMF (25ml_) and pyridine (2.2ml_, 2.73mnnol) to a suspension. Adipoyl-chloride (0.4mL, 2.73mnnol) dissolved in dimethylformannide (5mL) was added drop wise over 5 minutes to the stirring reaction mixture at 0°C to afford a clear solution. The reaction was stirred for 2h at 0°C, poured over water (10OmL) and acidified to pH~2 using 0.1 N hydrochloric acid solution while stirring. The white solid (Ampicillin-adipic diacid,) that formed was isolated by vacuum filtration, washed with water (2x50ml_) and dried overnight under vacuum at room temperature. Ampicillin-adipic diacid. Yield: 50% (white powder). 1 H NMR (DMSOc/6): δ 9.10 (d, 2H, NH), 8.50 (d, 2H, NH), 7.45-7.20 (m, 10H, ArH), 5.75 (d, 2H, CH), 5.55-5.50 (m, 2H, CH), 5.40 (d, 2H, CH), 4.20 (s, 2H, CH), 2.25-2.20 (m, 4H, CH2), 1.65-1.35 (m, 4H, CH2), 1.20 (s, 12H, CH3). Mass= [M+H] 809.
3.3 Ampicillin-adipic diacid -Poly(anhydride-amide)
[07] Ampicillin-adipic diacid (1.3g, 1.60mmol) was dissolved in CH2CI2 (2OmL) and thethylamine (0.72mL, 7.07mmol). Thphosgene (0.4Og, 1.36mmol) dissolved in dichloromethane (5mL) was added drop wise over 15 minutes to the stirring reaction mixture at 0°C to afford a suspension. The reaction was stirred for 2h at 0°C under nitrogen and poured over diethyl ether (5OmL). The solid (poly- ampicillin-adipic) that formed was isolated by vacuum filtration, washed with acidic water (2x50mL) and dried overnight under vacuum at room temperature. PoIy- ampicillin-adipic. Yield: quantitative (dark yellow powder). 1 H NMR (DMSO-c/6): δ 9.10 (d, 2H, NH), 8.45 (d, 2H, NH), 7.45-7.20 (m, 10H, ArH), 5.75 (d, 2H, CH), 5.55- 5.50 (m, 2H, CH), 5.35 (d, 2H, CH), 4.20 (s, 2H, CH), 2.25-2.20 (m, 4H, CH2), 1.60- 1.30 (m, 4H, CH2), 1.15 (s, 12H, CH3). Melting point = 94°C. Example 3
Synthesis Scheme: 3
Figure imgf000035_0001
3.4 Poly-Paclitaxel-Sebacoyl
[08] Paclitaxel (0.2g, 0.23mmol) was dissolved in CH2CI2 (2OmL) and triethylamine (0.13g, 0.93mnnol) to a suspension, sebacoyl-chlohde (0.56mL, 0.23mnnol) dissolved in CH2CI2 (2OmL) was added drop wise over 15 minutes to the stirring reaction mixture at 0°C. The reaction mixture was stirred for 3h at 0°C under nitrogen and poured over DCM (5OmL). Washed with acidic water (2x50mL) and dried over Na2SO4 filtered, concentrated under vacuum and the crude compound was purified by pre-HPLC to afford Poly-paclitaxel-sebacoyl. Yield: quantitative (white powder). 1 H NMR (500MHz, CDCI3): δ 8.14 (d, 2H, ArH), 7.75 (d, 2H, ArH), 7.70-7.32 (m, 11 H, ArH), 6.90 (d, 1 H, CH), 6.30-620 (m, 2H, CH), 5.95 (dd, 1 H, CH), 5.69 (d, 1 H, CH), 5.50 (d, 1 H, CH), 4.90 (d, 1 H, CH), 4.42 (t, 1 H, CH). 4.31 (d, 1 H, CH), 4.20 (d, 1 H, CH), 3.81 (d, 1 H, CH), 2.60-1.15 (m, 37H). Mw = 10082, PDI = 1.01. DSC= 147°C. [09] Other linker reagents, such as triphosgene, can be substituted for sebacoyl chloride to provide a carbonate-derived linker. Alternatively, a mixture of triphosgene and sebacoyl chloride can be used as linker reagents to provide a linker of carbonate- and sebacoyl-derived linkers.
Example 4
Synthesis Scheme: 4
Figure imgf000036_0001
3.5 Poly-Paclitaxel- adipic
[10] Paclitaxel (0.2g, 0.23mmol) was dissolved in CH2CI2 (2OmL) and triethylamine (0.13ml_, 0.93mmol) to a suspension. Adipoyl-chloride (0.03ml_, 0.23mmol) dissolved in CH2CI2 (5ml_) was added drop wise over 15 minutes to the stirring reaction mixture at 0°C. The reaction mixture was stirred for 2h at 0°C under nitrogen and poured over DCM (5OmL). Washed with acidic water (2x50mL) and dried over Na2SO4 filtered, concentrated under vacuum and the crude compound was purified by pre-HPLC to afford Poly-paclitaxel-adipic. Yield: 50% (white powder). 1 H NMR (500 MHz, CDCI3): δ 8.14 (d, 2H, ArH), 7.75 (d, 2H, ArH), 7.70-7.32 (m, 11 H, ArH), 6.90 (d, 1 H, CH), 6.30-620 (m, 2H, CH), 5.95 (dd, 1 H, CH), 5.69 (d, 1 H, CH), 5.50 (d, 1 H, CH), 4.90 (d, 1 H, CH), 4.42 (t, 1 H, CH). 4.31 (d, 1 H, CH), 4.20 (d, 1 H, CH), 3.81 (d, 1 H, CH), 2.60-1.15 (m, 33H). Mw = 9406, PDI = 1.01. DSC=2170C.
Example 5
Synthesis Scheme: 5
Figure imgf000037_0001
3.6 Paclitaxel-Succinic diacid
[11] Paclitaxel (100mg, O.U mmol) was dissolved in DCM (2OmL), was added TEA (0.032ml_, 0.23mmol) followed by DMAP (28mg, 0.23mmol). Succinic anhydride (23mg, 0.23mmol) dissolved in DCM (5ml_) was added drop wise to the stirring reaction mixture at 0°C to afford a clear solution. The reaction was stirred for overnight at room temperature, the reaction mixture was concentrated under vacuum and the crude compound was purified by column chromatography to afford paclitaxel-succinic diacid. Yield: 35% (white powder). 1 H NMR (500 MHz, CDCI3): δ 8.16 (d, 2H, ArH), 7.77 (d, 2H, ArH), 7.65-7.30 (m, 11 H, ArH), 6.70 (d, 1 H, CH), 6.30- 620 (m, 2H, CH), 5.95 (d, 1 H, CH), 5.69 (d, 1 H, CH), 5.50 (d, 1 H, CH), 4.90 (d, 1 H, CH), 4.42 (t, 1 H, CH). 4.31 (d, 1 H, CH), 4.20 (d, 1 H, CH), 3.81 (d, 1 H, CH), 2.80- 1.15 (m, 31 H).
3.7 Poly-Paclitaxel- Succinic
[12] Paclitaxel-succinic diacid (40mg, 0.03mmol) was dissolved in CH2CI2 (1OmL) and triethylamine (0.02ml_, 0.15mmol). Triphosgene (12mg, 0.04mmol) dissolved in dichloromethane (5ml_) was added drop wise over 15 minutes to the stirring reaction mixture at 0°C to afford a suspension. The reaction was stirred for 6h at 0°C under nitrogen and poured over DCM (5OmL). Washed with acidic water (2x25mL) and dried over Na2SO4 filtered, concentrated under vacuum and the crude compound TLC shows no. of spots, after column purifications compounds its self decompose.
Example 6
Scheme: 6
Figure imgf000038_0001
3.8 Paclitaxel- Butyric acid
[13] This reaction and analysis were conducted to determine the relative activity of potentially reactive site on the paclitaxel molecule.
[14] Paclitaxel (100mg, 0.11 mmol) was dissolved in DCM (2OmL), was added EDCI (44mg, 0.23mmol) followed by DMAP (28mg, 0.23mmol). Butyric acid (0.02ml_, 0.23mnnol) dissolved in DCM (5ml_) was added drop wise to the stirring reaction mixture at 0°C to afford a clear solution. The reaction was stirred for overnight at room temperature under nitrogen and poured over DCM (5OmL). Washed with water (2x50ml_) and dried over Na2SO4 filtered, concentrated under vacuum and the crude compound was purified by column chromatography to afford paclitaxel- butyric ester. Yield: 66% (white powder). 1 H NMR (500 MHz, CDCI3): δ 8.17 (d, 2H, ArH), 7.77 (d, 2H, ArH), 7.65-7.30 (m, 11 H, ArH), 6.82 (d, 1 H, CH), 6.30- 620 (m, 2H, CH), 5.95 (d, 1 H, CH), 5.69 (d, 1 H, CH), 5.50 (d, 1 H, CH), 4.95 (d, 1 H, CH), 4.42 (m, 1 H, CH). 4.35 (d, 1 H, CH), 4.21 (d, 1 H, CH), 3.81 (d, 1 H, CH), 2.60- 1.15 (m, 31 H), 0.90 (t, 6H1 CH3).
Example 7
Synthesis Scheme: 7
Figure imgf000039_0001
3.9 Poly-Rapamycin-adipic
[15] Rapamycin (0.2g, 0.22mmol) was dissolved in CH2CI2 (2OmL) and triethylamine (0.12ml_, 10.87mnnol) to a suspension. Adipoyl-chloride (0.03mL, 0.22mnnol) dissolved in CH2CI2 (5ml_) was added drop wise over 15 minutes to the stirring reaction mixture at 0°C. The reaction mixture was stirred for 2h at 0°C under nitrogen and poured over DCM (5OmL). Washed with acidic water (2x50mL) and dried over Na2SO4 filtered, concentrated under vacuum and the crude compound was purified by pre.HPLC to afford Poly-rapamycin-adipic. Yield: 6% (white powder). Mw = 5213, PDI = 1.01.
Example 8
3.10 Poly-PEG(600 daltons)-Paclitaxel
Synthesis Scheme 8:
Figure imgf000041_0001
Synthesis:
[16] 0.461 g (0.643m. mol) of PEG-diacid(600 daltons) was azeotroped with dry toluene(100ml) and was dissolved in anhydrous dichloromethane(50ml) under nitrogen. Then cool the mixture to 0°C, at 0°C diisopropylcarbodiimide (DIPC) (0.18ml, 1.16m. mol) was added and stirred for 5 min. Paclitaxel (0.5g,0.586mmol) and DMAP (35mg.0.286m. mol) were added one by one to the above reaction mixture. Maintained the reaction mixture at 0°C for 3h. The reaction was monitor by HPLC. After completion of the reaction, the reaction mixture was diluted with DCM(25ml) and washed with 0.1 N HCI (5OmL). The separated organic layer was dried over Na2SO4, concentrated under vacuum at 250C to obtained 1.2g of crude compound. After purification through pre-HPLC to afford 100mg (20%yeild) of PoIy- [PEG (600daltons)-paclitaxel] with 97.79% purity by HPLC.
Results: Yield: The yield obtained was 20% (off white powder).

Claims

1. A composition comprising a biodegradable polymer, the biodegradable polymer being linked to a chemical moiety through at least one covalent bond, wherein, the chemical moiety forms a pharmaceutically active agent upon degradation of the covalent bond, the polymer is less soluble in an aqueous medium than the free form of the pharmaceutically active agent, and the polymer has a Tg greater than 50°C.
2. The composition of claim 1 , wherein the Tg is greater than 60°C.
3. The composition of claim 1 , wherein the at least one covalent bond is hydrolytically degradable.
4. The composition of claim 1 , wherein the biodegradable polymer comprises at least one monomehc unit selected from lactic acid, glycolic acid, caprolactone, lactide, glycolide, and trimethyl carbonate.
5. The composition of claim 1 , wherein the chemical moiety is linked to the biodegradable polymer via a linking group.
6. The composition of claim 1 , wherein the covalent bond is selected from anhydride and ester bonds.
7. The composition of claim 1 , wherein the chemical moiety is linked to the biodegradable polymer as a pendant group of the polymer chain.
8. The composition of claim 1 , wherein the chemical moiety is a portion of the polymer backbone.
9. The composition of claim 1 , wherein the covalent bond is hydrolytically degradable.
10. The composition of claim 1 , wherein the biodegradable polymer is present in an amount ranging from 40% to 95% by weight relative to the total weight of the composition.
11. The composition of claim 1 , wherein the number average molecular weight of the polymer is 25,000 Da or less.
12. The composition of claim 1 , wherein the number average molecular weight of the polymer ranges from 25,000 Da to 100,000 Da.
13. The composition of claim 1 , wherein the pharmaceutically active agent released is selected from taxanes, limus derivatives, and non-steroidal antiinflammatory agents.
14. The composition of claim 1 , wherein the pharmaceutically active agent released is selected from paclitaxel, sirolimus, everolimus, and biolimus.
15. The composition of claim 1 , wherein the pharmaceutically active agent released is hydrophobic.
16. A medical device having at least one coating covering at least a portion of the device, the at least one coating comprising the composition of claim 1.
17. The device of claim 16, wherein the at least one coating comprises at least two coatings to provide a multi-layered structure.
18. The device of claim 16, wherein the at least one coating comprises at least three coatings.
19. The device of claim 18, wherein each of the at least three coatings provides a different chemical moiety that forms a different pharmaceutically active agent.
20. The device of claim 19, wherein the composition in one of the at least three coatings comprises a chemical moiety that forms an antiproliferative pharmaceutically active agent.
21. The device of claim 19, wherein the composition in one of the at least three coatings comprises a chemical moiety that forms an anti-inflammatory agent.
22. The device of claim 19, wherein the composition in one of the at least three coatings comprises a chemical moiety that forms a healing promoter.
23. The device of claim 16, wherein the at least one coating directly contacts the device.
24. The device of claim 16, further comprising an inner coating free of a pharmaceutically active agent that directly contacts the device, wherein the inner coating also directly contacts the at least one coating.
25. The device of claim 16, wherein the chemical moiety is present in a dose density ranging from 0.05 to 10 μg/mm2.
26. The device of claim 16, wherein the device is implantable into a mammalian lumen.
27. The device of claim 16, wherein the device is a stent.
28. The device of claim 27, wherein the stent is either balloon expandable or self-expanding.
29. The device of claim 16, wherein the coating is a conformal coating around all surfaces of the stent.
30. The device of claim 16, wherein the coating is coated only on the abluminal surface of the stent.
31. The device of claim 16, wherein the coating is coated only on the abluminal surface of the stent and the composition resides partially or completely within micro-reservoirs or pores in the stent surface.
32. The device of claim 16, wherein the device is selected from pacemaker leads, valve replacement and repair devices, vena cava filters, and embolic coils and beads.
33. The device of claim 16, wherein the device is an angioplasty balloon, wherein the balloon is used to deliver the composition to an endoluminal surface.
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